Method for relieving sinus congestion

ABSTRACT

A method for temporarily relieving sinus congestion and pressure comprising administering to a human a dose of a multi-particle pulsatile oral dosage form with an immediate release form and a plurality of delayed release particles. The immediate release form contains about 10 mg phenylephrine hydrochloride. The delayed release form contains a core with coatings including a phenylephrine coating containing about 10 mg phenylephrine hydrochloride and a pH sensitive coating.

FIELD OF THE INVENTION

The present invention is generally related to a method of relievingsinus congestion for at least eight hours by administering a dosage formcontaining immediate and delayed release phenylephrine particles andmore particularly, where the delayed release of phenylephrine ispulsatile.

BACKGROUND OF THE INVENTION

Decongestants are commonly used to relieve nasal congestion and acommonly used decongestant is phenylephrine. Phenylephrine is widelyavailable to consumers as an over-the-counter (OTC) drug.

One problem for immediate release dosage forms containing phenylephrineis that in order for it to be most effective, it must be takenfrequently. The current U.S. Monograph for an oral dosage formcomprising phenylephrine hydrochloride is ten milligrams every fourhours.

Consumers find it inconvenient to dose every four hours and frequentlymiss doses, especially mid-day doses, which can result in poorsymptomatic relief.

Furthermore, the short time period between doses makes it difficult tocombine phenylephrine with other drug actives, in particular activesthat are commonly used in multi-symptom relief cold/flu products, whichhave longer dosing intervals. Therefore, consumers have to take multipledosage forms and dose several times a day at various intervals toexperience the optimal relief of their cold/flu symptoms.

One of the reasons for frequent dosing is because phenylephrine issubject to high first pass metabolism and a short half-life. Upon oraladministration, phenylephrine is rapidly metabolized and is subsequentlyconjugated into sulfate and glucuronide forms. However, the therapeuticdecongestant activity is attributed to the portion of the phenylephrinethat is not metabolized and stays as the unconjugated parent active.Accordingly, it is of benefit to maximize the duration of time of theunconjugated active form present in bloodstream after oraladministration.

There have been several attempts to modify the release of phenylephrinein order to prolong the dosing interval. Many approaches related to themodified release of phenylephrine focus on dual release mechanismscomprising an immediate release form coupled with an extendedfirst-order or zero-order extended phase of release. A problem withthese bi-modal approaches is that during the extended release phase, lowlevels of unconjugated phenylephrine active are likely to be present inthe bloodstream due to rapid first pass metabolism. An alternateapproach would be a pulsatile dose form that releases active atdifferent regions in the intestine and can mimic immediate releasedosage forms administered every 4 hours. Such a dosage form would bebeneficial to the consumer and allow for more effective and convenientdosing.

As such, there remains a need in the area of consumer selected OTCtherapies for improved options for the treatment of symptoms associatedwith the common cold (rhinovirus), influenza, or environmentalallergies. In particular, there exists a need for a convenient longeracting phenylephrine dosage form that can provide relief over anextended period of time relative to current therapies.

SUMMARY OF THE INVENTION

A method for temporarily relieving sinus congestion and pressurecomprising administering to a human a dose of a multi-particle pulsatileoral dosage form comprising: (a) an immediate release form comprisingabout 10 mg phenylephrine hydrochloride; and (b) a plurality of delayedrelease particles wherein each delayed release particle comprises: (i) acore wherein at least about 85% of the cores comprise a diameter fromabout 500 μm to about 710 μm; (ii) a phenylephrine coating comprisingphenylephrine hydrochloride; (iii) a pH sensitive coating comprising anacrylate copolymer selected from the group consisting ofmethyl-methacrylate esters copolymerized with methacrylic acid, acrylicacid and esters copolymerized with methacrylic acid and esters,ammonio-containing acrylate copolymers, and combinations thereof;wherein the pH sensitive coating is from 40 μm to about 80 μm thick;wherein the plurality of delayed release particles comprise about 10 mgmg phenylephrine hydrochloride.

A method for temporarily relieving sinus congestion and pressurecomprising administering to a human a dose of a multi-particle pulsatileoral dosage form comprising: (a) an immediate release form comprisingabout 10 mg phenylephrine hydrochloride; and (b) a plurality of delayedrelease particles wherein each delayed release particle comprises: (i) acore; (ii) a phenylephrine coating comprising phenylephrinehydrochloride; (iii) a pH sensitive coating wherein the pH sensitivecoating comprises an enteric coating; wherein the pH sensitive coatingis from 40 μm to about 80 μm thick; wherein the plurality of delayedrelease particles comprise from about 7 mg to about 15 mg phenylephrinehydrochloride; wherein the pulsatile dosage form comprises a C_(max2)and an AUC₄₋₈ wherein an upper bound of a 90% confidence interval for aratio of means for the C_(max2) and the AUC₄₋₈ of the pulsatile dosageform relative to two sequential doses of an immediate releasephenylephrine taken four hours apart is at least 85%.

A method for temporarily relieving sinus congestion and pressurecomprising administering to a human a dose of a multi-particle pulsatileoral dosage form comprising: (a) an immediate release form comprisingphenylephrine hydrochloride; and (b) a plurality of delayed releaseparticles wherein each delayed release particle comprises: (i) a core;(ii) a phenylephrine coating comprising phenylephrine hydrochloride;(iii) a pH sensitive coating wherein the pH sensitive coating isdegradable at a pH from about 6 to about 8; wherein the plurality ofdelayed release particles comprise from about 7 mg to about 20 mgphenylephrine hydrochloride; wherein the ratio of the amount ofphenylephrine in the immediate release form to the amount ofphenylephrine in the delayed release form is from about 1.5:1 to about1:1.5; wherein the pulsatile dosage form comprises an AUC₀₋₄ and anAUC₄₋₈ wherein a mean AUC₀₋₄ and a mean AUC₄₋₈ of the pulsatile dosageform meets or exceeds a mean AUC₀₋₄ and a mean AUC₄₋₈ of two sequentialdoses of an immediate release phenylephrine taken four hours apart.

BRIEF DESCRIPTION OF THE DRAWINGS

While the specification concludes with claims particularly pointing outand distinctly claiming the subject matter of the present invention, itis believed that the invention can be more readily understood from thefollowing description taken in connection with the accompanyingdrawings, in which:

FIG. 1 is a schematic of an immediate release particle;

FIG. 2 is a schematic of a delayed release particle;

FIG. 3 shows the mean concentration of unconjugated phenylephrine, invivo over time for different formulation prototypes;

FIG. 4 shows the mean concentration of total phenylephrine, in vivo overtime for different formulation prototypes;

FIG. 5A shows the mean unconjugated phenylephrine concentration forExample 3, Treatments A, B, and C versus Reference Treatment F;

FIG. 5B shows the mean unconjugated phenylephrine concentration forExample 3, Treatments A, D, and E versus Reference Treatment F;

FIG. 5C shows the mean unconjugated phenylephrine concentration forExample 3, Treatment A versus Reference Treatment F;

FIG. 6 shows the mean percent dissolved phenylephrine, in vitro usingthe Krebs Buffer Dissolution Method, over time for different formulationprototypes;

FIGS. 7A, 7B, 7C, and 7D show digital photographs of delayed releaseparticles under a total magnification of 40×;

FIGS. 8A, 8B, 8C, and 8D show digital photographs of delayed releaseparticles under a total magnification of 40×; and

FIGS. 9A and 9B show exemplary images of the field of view used in theSmoothness Test Method.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a multi-particle, oral dose formdesigned for an immediate release of phenylephrine hydrochloride (PE)followed by one or more delayed pulses. In one example, one or moredelayed pulses are formulated so the phenylephrine is released in adifferent region of the gastrointestinal tract in order to provide anextended period of congestion relief. In one example, the delayeddelivery doses are enteric coated and designed to release thephenylephrine in the distal small intestine. While not wishing to bebound by theory, it is believed that delivery to the distal smallintestine is effective because the effects of the operative metabolicenzymes are reduced, ultimately resulting in an optimal amount ofunconjugated phenylephrine in the blood and longer duration of dosing.In this way, therapeutic levels of phenylephrine can be delivered at theappropriate dose, intestinal region, and time interval to provideeffective relief over an extended period of time.

The multi-particle, solid oral dose form can be a tablet, a sachet, or acapsule, containing phenylephrine which can be administered every 6, 8,or 12 hours to provide extended congestion relief to a patient. In oneexample, the dose form can meet or exceed the bioavailability and/orbioequivalence as compared to two or three immediate release doses ofphenylephrine taken at four hour time intervals.

As used herein, “AUC” refers to the area under the concentration-timecurve from time of dosing up to a time point, calculated by the lineartrapezoidal rule. AUC is a parameter that shows the cumulative plasmaconcentration of a drug over time, and is an indicator of the totalamount and availability of a drug. “AUC_((0-t)”) is defined as AUC forany value of time up to t hours. In one example, t is 12 hours (referredto herein as AUC₍₀₋₁₂₎, other examples can include AUC₍₀₋₄₎, andAUC₍₀₋₈₎. “AUC₍₄₋₈₎” refers to AUC between four and eight hours afterdosing. “AUC_((0-inf))” is defined as calculated AUC extrapolated toinfinity. AUC_((0-inf)), is calculated as equal to AUC_(last)+Ct/lambdaz, wherein AUC_(last) is the AUC until the time point of last measurableconcentration, Ct is the last measurable plasma concentration, andlambda z is the terminal phase rate constant. Terminal phase rateconstant lambda z is derived from the slope of the drugconcentration-time curve using linear regression on terminal data pointsof the curve.

As used herein, “bioavailability” refers to a rate and extent to whichthe active drug ingredient or therapeutic moiety is absorbed from a drugproduct and becomes available for therapeutic action. In one example thedrug ingredient can be phenylephrine and it can reach the systemiccirculation and can be available at its site of action.

As used herein, “bioequivalent” and “bioequivalency” refers to a dosageform whose rate and extent of absorption do not show a significantdifference when administered under similar experimental conditions, to asingle dose or multiple doses of a currently available product. Somedosage forms may be equivalent in the extent of their absorption but notin their rate of absorption and yet may be considered bioequivalentbecause such differences in the rate of absorption are intentional andare reflected in the labeling, are not essential to the attainment ofeffective body drug concentrations on chronic use, or are consideredmedically insignificant for the particular drug product studied. Apulsatile PE dose form can meet or exceed the bioequivalence limits of acommercially available, immediate release PE dose taken at 4 hourintervals (reference product). To demonstrate bioequivalence thepulsatile PE dose form (T) is compared to the reference IR product (R)and the 90% confidence intervals for the geometric mean T/R ratios forthe parameters, including C_(max), AUC_(0-last) and AUC_(0-inf) fallwithin the limits of 80.00-125.00%.

As used herein, “conjugated phenylephrine” refers to phenylephrine thatis metabolized. This means that the phenylephrine has been conjugated(i.e. chemically altered) by an enzyme. The enzymes which conjugatephenylephrine can include sulfotransferase orUDP-glucuronosyltransferase.

As used herein “delayed release” refers to a particle, a plurality ofparticles, or a dosage form where the drug active (or actives) arereleased at a time other than immediately following oral administration.In one example, a delayed release particle, plurality of particles, ordosage form has been deliberately modified such that the majority of thedrug active that is contained in or on the particle, plurality ofparticles, or dosage form is released or absorbed into the blood plasmasome period of time after administration. One advantage of a delayedrelease dosage form is that it can be formulated to release an activeafter a specified time period or upon encountering the properenvironment (for example, release based on pH, enzymatic activity, orsolubility). In one example, the delayed release particles have anenteric coating, which means that the particle coatings are pH sensitiveand the benefit is not experienced by the user until the particle(s) ordosage form reaches certain regions of the intestine. In one example, adelayed release particle, plurality of particles, or a dosage form canbe taken in combination with an immediate release for, which can includean immediate release particle, plurality of particles or other dosageform. In one example, the dosage form or particle(s) do not deliver anactive slowly over an extended duration of time, instead the particlescan be designed to rapidly or immediately deliver an active after adelay period.

As used herein, “dissolve” refers to disintegrating, dispersing and/orpassing into solution.

As used herein, “dose” or “dosage unit” refers to a dosage formcontaining an amount of a drug active suitable for administration on asingle occasion, according to sound medical practice.

The dosage form may include a variety of orally administered dosageforms. Non-limiting examples of dosage forms can include particlessuspended in a liquid formulation, a solid in a gelatin or foam, or asolid dose in the form of a tablet, powder, granules, pellets,microspheres, nanospheres, beads, or nonpareils, and combinationsthereof. In one example, the dosage form is a tablet or a capsule. Inanother example, the dosage form is a capsule containing delayed releaseparticles and optionally an immediate release form and excipients.Dosage forms can be orally administered and are typically swallowedimmediately, slowly dissolved in the mouth, or chewed.

As used herein, “extended release” (ER) refers to a particle, aplurality of particles, or a dosage unit that allows a reduction indosing frequency as compared to that presented by a conventional dosageform, e.g., a solution or an immediate release dosage form. In oneexample, an extended release dosage form can be deliberately modifiedwherein the particle, plurality of particles, or dosage form isformulated in such a manner as to make the drug active available over anextended period of time following administration. One example of anextended release particle, plurality of particles or dosage form is adelayed release (DR) dosage form. Another example of an extended releaseparticle, plurality of particles or dosage form can be pulsatile releasedosage forms or particle(s).

As used herein, “immediate release” (IR) refers to a particle, aplurality of particles, or a dosage form wherein no deliberate efforthas been made to modify the release rate and in the case of capsules,tablets, and particles the inclusion of a disintegrating agent is notinterpreted as a modification.

As used herein, “PK profile” refers to a pharmacokinetic profile whichis the concentration of a drug, such as unconjugated phenylephrine, inplasma over time.

As used herein, “pulsatile release” refers to the phenylephrine beingreleased at two or more distinct time periods following ingestion. Inone example, the dosage form can have an immediate release form, whichcan be a plurality of immediate release particles, and a plurality ofdelayed release particles which results in an immediate release of thefirst pulse of phenylephrine after administration of the dosage form tothe user and a second pulse when the delayed release particles enter thehigher pH environment of the small intestine.

As used herein, the term “substantially equivalent” refers to withinabout 60% of the reference treatment (e.g. ratio of means are ≥60%), inanother example within about 70%, in another example within about 75%,in another example within about 80%, in another example within about85%, in another within about 90%, in another example within about 93%,in another example within about 95%, in another example within about98%, in another example within about 102%, in another example withinabout 105%, in another example within about 107%, in another examplewithin about 110%, in another example within about 115%, in anotherexample within about 120%, in another example within about 125%, inanother example within about 130%, and in another example within about140%. Substantially equivalent can refer to, but is not limited to, thePK profile, C_(max), C_(max1), C_(max2), and AUC including AUC₀₋₄ andAUC₄₋₈.

As used herein, the term “total phenylephrine” refers to the amount ofconjugated phenylephrine and unconjugated phenylephrine.

As used herein, the term “treat” or “treating” includes preventing,alleviating, ameliorating, inhibiting, or mitigating one or more healthconditions in a mammal. Non-limiting examples of health conditions caninclude respiratory conditions.

As used herein, “unconjugated phenylephrine” refers to phenylephrinethat is unmetabolized and is the therapeutically active form ofphenylephrine. Unmetabolized phenylephrine is phenylephrine that hasentered the body of the user and is not chemically altered at the timeof absorption into the blood plasma or later.

As used herein, the articles “a” and “an” are understood to mean one ormore of the material that is claimed or described, for example, “anacrylic acid ester co-polymer” or “a multi-particle dosage form”.

All percentages, parts and ratios as used herein are by weight of thedosage form, unless otherwise specified. All such weights as theypertain to listed ingredients are based on the active level and,therefore do not include solvents or by-products that may be included incommercially available materials, unless otherwise specified.

The dosage form, process and methods of the present invention cancontain, consist of, or consist essentially of, the essential elementsand limitations of the invention described herein, as well as anyadditional or optional ingredients, components, or limitations describedherein or otherwise useful in dosage forms intended for use orconsumption by humans.

FIG. 1 shows a schematic of an immediate release particle 1. Immediaterelease particle 1 can comprise a core 2, a phenylephrine coating 3, andoptionally a separation coating 4. In one example, the phenylephrinecoating 3 can dissolve or start to dissolve after it reaches thestomach.

An optional anti-caking coating can be added to immediate releaseparticles and is not shown in FIG. 1.

FIG. 2 shows a schematic of a delayed release particle 10. Delayedrelease particle 10 comprises a core 12, phenylephrine coating 13,optionally separation coating 14, pH sensitive coating 15, andoptionally anti-caking coating 16.

In one example, the immediate release particles and/or the delayedrelease particles can have a separation coating. For immediate releaseparticles the separation coating can help limit friability in handlingthe particles. Additionally, for delayed release particles theseparation coating can separate the highly soluble phenylephrine layerfrom the pH sensitive coating. If phenylephrine leaches or migrates intothe pH sensitive coating then this may result in premature drugdissolution.

Non-limiting examples of separation coatings can include talc, polyvinylalcohol-polyethylene glycol graft co-polymer (commercially available asKollicoat® IR, from BASF, Tarrytown, N.J.), hydroxypropylymethylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidine, andcombinations thereof. In another example, the separation coating can bea pH independent polymer. In another example, the separation coating canbe a pH independent polymer. In one example, the separation coating cancontain polyvinyl alcohol.

In one example, the anti-caking coating can be sprayed onto the delayedrelease particles to prevent the particles from sticking together duringstorage. In another example, the immediate release particles can have ananti-caking coating. If the particles stick together, this can causeuneven dissolution, which alters the carefully timed release of thephenylephrine. The anti-caking coating can be any material that preventsthe particles from sticking together. In one example, the anti-cakingcoating can be clear and in another example the anti-caking coating canbe translucent. In another example, the anti-caking coating can beopaque. In another example, the anti-caking coating can be a whitepowder. In another example, the anti-caking coating can contain a color.In one example, the anti-caking coating can contain a fine particulatethat has a high relatively high surface area and is insoluble in water.In one example the surfaces area is greater than about 100 m²/g, inanother example greater than about 150 m²/g, in another example greaterthan about 175 m²/g, and in another example greater than about 200 m²/g.In one example, the weight percent (wt. %) increase of the particleafter the anti-caking coating is added can be from about 0.1% to about5%, in another example from about 0.15% to about 3%, and in anotherexample from about 0.2% to about 2%.

Non-limiting examples of anti-caking coatings can include talc, sodiumferrocyanide, potassium ferrocyanide, calcium carbonate, magnesiumcarbonate, silicon dioxide, hydrophilic fumed silica (commerciallyavailable as Aerosil® 200, Evonik Industries, Parsippany, N.J.),precipitated silica, sodium aluminosilicate, and combinations thereof.In one example, the anti-caking coating contains hydrophilic fumedsilica. In another example, the anti-caking coating can contain a thinaqueous coating based on glycerol monostearate and/or hydroxypropylmethylcellulose. In another example, the anti-caking coating can containpolyvinyl alcohol, and/or polyvinyl alcohol-polyethylene glycol graftcopolymer (commercially available as Kollicoat® IR, BASF, Tarrytown,N.J.).

Owing to the different pH environments and variability within the GItract, it can be difficult to predict the level and type of polymerrequired to affect the desired pulsed release characteristics. In oneexample, of a pulsed release phenylephrine dosage form, the polymertype, coating level, particle population ratios, and individual doselevels are carefully selected and tailored based on dissolution andpharmacokinetic parameters to achieve a dosage form with a PK profilethat meets or exceeds bioequivalence limits and/or bioavailabilityand/or is substantially equivalent relative to sequentially dosedimmediate release forms of phenylephrine taken at regular, usually fourhour, intervals.

An example, may include a mixture of immediate release forms and delayedrelease particles at dosages that are not bioequivalent to sequentiallydosed immediate release forms but can nevertheless be registered in theUS and other geographies through appropriately designed clinicalpharmacokinetic, safety and/or efficacy trials or additional supportingdata. Another example can include a mixture of immediate release anddelayed release particles at dosages that are substantiallybioequivalent to two or three sequentially dosed immediate releaseddosage forms.

The PK profile examines the time course in vivo after phenylephrine hasbeen administered and includes the C_(max), AUC, t_(lag), and t_(max).C_(max) is the maximal plasma concentration observed. t_(max) is thetime to reach C_(max). t_(lag) lag is the lag time prior to the firstquantifiable plasma concentration level. Other parameters of interestcan include partial area under the curves including AUC₍₀₋₄₎ andAUC₍₄₋₈₎; plasma concentration values at 4 and 8 hours post-dose(C_(4hr) and C_(8hr)); C_(max) which refers to the maximum plasmaconcentration over the entire dosing interval; C_(max1) which refers tothe maximum plasma concentration that occurs between 0 and 2 hours afterdosing; and C_(max2) which refers to the maximum plasma concentrationthat occurs between 2 and 12 hours after dosing.

Example 1

PK parameters for unconjugated and total PE from an in vivo study thatevaluated four delayed release treatments to a commercially availablephenylephrine product are shown in Table 1 and Table 2 and FIGS. 3 and4. Treatments 1-6 are further described in Table 10, hereafter.Treatments 5 and 6 used a commercially available phenylephrine product,Equate® Non-Drowsy Suphedrine PE (Batch No. 1DE1383). Treatment 5 wasadministered once at t=0 hours. Treatment 6 was administered threetimes, once at t=0, once at t=4, and then again at t=8.

Table 1, which is detailed below, shows a summary of the key PKparameters in vivo, C_(max), AUC_(last), t_(lag), and t_(max), forunconjugated PE.

TABLE 1 C_(max) AUC_(last) t_(lag) t_(max) Treatment (pg/mL) (pg ·hr/mL) (h) (h) 1 1294 (75.4) 1481 (83.4) 1 (0.5, 2.5) 3 (2, 4) 2 1728(95.4) 1872 (57.8) 2.5 (1, 3.5) 3.5 (1.5, 8) 3 1978 (77.9) 2325 (60.8)2.5 (0.3, 4.5) 3.5 (2.5, 5.5) 4 1444 (64.5) 1824 (41.5) 2 (1, 3) 3.25(2.5, 4) 5 689 (54.4)  632 (21.0) 0 (0, 0) 0.5 (0.25, 0.53) 6 798 (33.4)2210 (20.9) 0 (0, 0) 0.5 (0.25, 1)* Mean (CV %) for C_(max), AUC andMedian (range) for t_(lag) and t_(max) *For Treatment 6, t_(max) valuesdisplayed are corrected for dosing time

Table 2, which is detailed below, shows a summary of the key PKparameters in vivo, C_(max), AUC_(last), t_(lag), and t_(max), for totalPE.

TABLE 2 Ratio of AUC_(last) Of unconjugated to C_(max) AUC_(last)AUC_(last) total t_(lag) t_(max) Treatment (ng/mL) (ng · hr/mL)phenylephrine (h) (h) 1 139 (29.6) 479 (22.1)  0.003 (103.9) 0.5 (0.25,0.5) 3 (2, 5) 2 63 (50.0) 269 (38.3) 0.008 (72.6) 2 (1, 3) 4 (2, 8) 3 73(41.1) 303 (26.1) 0.008 (73.0) 0.5 (0.25, 0.5) 4 (3, 6.5) 4 75 (54.4)323 (33.5) 0.006 (52.4) 0.358 (0.25, 0.5) 4 (2.5, 5.5) 5 163 (20.7) 570(15.6) 0.001 (30.4) 0 (0, 0) 1 (0.5, 2.0) 6 206 (17.2) 1795 (22.7) 0.001 (22.2) 0 (0, 0) 1.5 (1, 2.5) Mean (CV %) for C_(max,) AUC, andratio and Median (range) for t_(lag) and t_(max) *For Treatment 6,t_(max) values displayed are corrected for dosing time.

FIG. 3 shows the mean concentration of unconjugated phenylephrine overtime for different treatments. One example of a desired treatment can beone where the second pulse has a substantially equivalent C_(max),AUC_(last), t_(lag), and t_(max) to Treatment 6.

FIG. 4 shows the mean concentration of total phenylephrine over time fordifferent treatments. One example of a desired treatment can be onewhere the second pulse has a substantially equivalent C_(max),AUC_(last), t_(lag), and t_(max) to Treatment 6.

The treatments demonstrate that the ratio of AUC_(last) unconjugated toAUC_(last) of total phenylephrine is higher for the treatments with a pHsensitive coating than Treatments 5 and 6 which do not have a pHsensitive coating. In one example, the ratio for the treatments with apH sensitive coating is from twofold to tenfold greater than the ratioof a treatment without a pH sensitive coating, in another examplefourfold to eightfold greater, and in another example fivefold tosevenfold greater. In one example, the ratio for the treatment with a pHsensitive coating is six fold greater than the ratio of a treatmentwithout a pH sensitive coating.

The mean concentration of phenylephrine of Treatment 4 is the closest toTreatment 6 as compared to Treatments 1, 2, and 3. Thus, Treatment 4 wasused as a starting point to develop additional prototypes. However, thephenylephrine was released prematurely from Treatment 4 and is thus notideal. Thus, new prototypes were designed with thicker pH sensitivecoatings, to further delay the lag time. It was estimated that it wouldbe most desirable to further delay the lag time by an additional 90-120minutes.

Example 2

Treatments A-F were made and tested in a randomized, open-label,7-treatment, 4-period, incomplete crossover in vivo study was performedwith 29 healthy adult subjects (male or female, aged 18 to 45 years).Subjects were dosed with study product (investigational treatment Athrough F and for reference Treatment G, see Table 3 below) and remainedon-site for 24 hours post-dosing. Food and activities were standardizedfor the duration that subjects were at the study site. There was aminimum of a 5-day washout period between treatments withpharmacokinetic blood sampling up to 24 hours post-dose for eachtreatment.

During confinement, subjects provided blood samples for PK analysis ofunconjugated phenylephrine levels at various time points, includingbefore dosing and up to 12 hours after dosing. Safety was assessedthrough adverse events (AEs), physical examinations, laboratoryevaluations and vital signs.

Each of the six multi-particulate composite prototype phenylephrineformulations (Treatments A through F) was an oral capsule comprised ofan immediate-release phenylephrine-coated particles component combinedwith a delayed-release phenylephrine-coated particles component.Treatments A-F are further described in Table 11 and Table 12,hereafter. The six formulations differed in that the delayed-releaseparticles components contained differing doses of phenylephrine HCl (3,5, or 7 mg) and differing amounts of enteric coating used on particles(expressed as relative weight gain compared to uncoated particles; being40, 50, or 60% w/w).

Reference Treatment G was 2 Equate™ Suphedrine (immediate-releasephenylephrine HCl 10 mg) doses administered 4 hours apart. Equate™Suphedrine PE, was supplied to the test site as commercially availabletablets (Lot #s 3LE1708 and 3LE1845, manufactured by Perrigo® Company[Allegan, Mich.]) with protocol specific labeling.

A summary of the investigational treatments is in Table 3 below.

TABLE 3 Investigational Treatments for Example 2 DR Particles IRParticles Enteric Coating Example 2 Dose PE Level Dose PE Total dose PETreatment (mg) (wt %) (mg) (mg) A 10 40 5 15 B 10 40 7 17 C 10 50 3 13 D10 50 5 15 E 10 50 7 17 F 10 60 5 15

Evaluations included overall C_(max), AUC₀₋₈, AUC_(0-last), AUC_(0-inf),partial areas AUC₍₀₋₄₎ and AUC₍₄₋₈₎, C_(max1), C_(max2), C_(4hr), andC_(8hr), Statistical comparisons for each of the extended-releasetreatments relative to the reference Treatment G for unconjugatedphenylephrine are summarized in Table 4, below.

TABLE 4 Pharmacokinetic Parameters and Statistical Comparisons forUnconjugated Phenylephrine T/R Ratio Test Reference of MeansComparison^(a) PK Parameter (T)^(b) (R)^(b) (%) 90% CI^(c) Treatment Avs G C_(max) (pg/mL) 854.7 728.4 117.3 (93.4, 147.4) 15 mg ER C_(max1)(pg/mL) 638.2 648.6 98.4 (87.5, 110.7) (10 mg IR 5 mg C_(max2) (pg/mL)632.7 595.8 106.2 (71.0, 158.8) DR 40% EC) C_(4 hr) (pg/mL) 87.7 20.9419.5 (224.8, 782.7)  vs Reference C_(8 hr) (pg/mL) 44.5 36.0 123.6(93.3, 163.7) AUC₀₋₈ (pg · hr/mL) 1414.6 1417.5 99.8 (86.9, 114.7)AUC₀₋₄ (pg · hr/mL) 802.3 688.1 116.6  (102, 133.2) AUC₄₋₈ (pg · hr/mL)537.2 702.9 76.4 (56.6, 103.1) AUC_(0-last) (pg · hr/mL) 1553.3 1513.1102.7 (90.8, 116.1) AUC_(0-inf) (pg · hr/mL) 1697.8 1593.6 106.5 (94.7,119.9) Treatment B vs G C_(max) (pg/mL) 858.8 728.4 117.9 (93.9, 148.0)17 mg ER C_(max1) (pg/mL) 682.2 648.6 105.2 (93.5, 118.3) (10 mg IR 7 mgC_(max2) (pg/mL) 565.5 595.8 94.9 (67.1, 134.3) DR 40% EC) C_(4 hr)(pg/mL) 110.3 20.9 527.8 (283.9, 782.7)  vs Reference C_(8 hr) (pg/mL)49.8 36.0 138.2 (104.4, 182.9)  AUC₀₋₈ (pg · hr/mL) 1465.7 1417.5 126.5(110.7, 144.5)  AUC₀₋₄ (pg · hr/mL) 870.1 688.1 116.6 (102.0, 133.2) AUC₄₋₈ (pg · hr/mL) 510.6 702.9 72.6 (56.9, 92.7)  AUC_(0-last) (pg ·hr/mL) 1642.2 1513.1 108.5 (96.0, 122.7) AUC_(0-inf) (pg · hr/mL) 1866.01593.6 117.1 (104.1, 131.8)  Treatment C vs G C_(max) (pg/mL) 660.4728.4 90.7 (72.2, 113.8) 13 mg ER C_(max1) (pg/mL) 616.7 648.6 95.1(84.5, 107.0) (10 mg IR 3 mg C_(max2) (pg/mL) 173.9 595.8 29.2 (18.4,46.2)  DR 50% EC) C_(4 hr) (pg/mL) 49.0 20.9 234.5 (126.1, 435.8)  vsReference C_(8 hr) (pg/mL) 23.5 36.0 65.3 (49.4, 86.5)  AUC₀₋₈ (pg ·hr/mL) 948.9 1417.5 66.9 (58.3, 76.9)  AUC₀₋₄ (pg · hr/mL) 691.1 688.1100.4 (87.9, 114.7) AUC₄₋₈ (pg · hr/mL) 212.4 702.9 30.2 (23.8, 38.3) AUC_(0-last) (pg · hr/mL) 1029.4 1513.1 68.0 (60.2, 76.9)  AUC_(0-inf)(pg · hr/mL) 1171.0 1593.6 73.5 (65.4, 82.5)  Treatment D vs G C_(max)(pg/mL) 730.9 728.4 100.3 (80.0, 125.9) 15 mg ER C_(max1) (pg/mL) 618.9648.6 95.4 (84.8, 107.3) (10 mg IR 5 mg C_(max2) (pg/mL) 577.8 595.897.0 (70.9, 132.7) DR 50% EC) C_(4 hr) (pg/mL) 110.0 20.9 526.3 (283.2,978.2)  vs Reference C_(8 hr) (pg/mL) 50.1 36.0 139.0 (105.0, 184.0) AUC₀₋₈ (pg · hr/mL) 1328.6 1417.5 93.7 (81.6, 107.6) AUC₀₋₄ (pg · hr/mL)835.6 688.1 121.4 (106.3, 138.7)  AUC₄₋₈ (pg · hr/mL) 464.9 702.9 66.1(52.3, 83.7)  AUC_(0-last) (pg · hr/mL) 1487.2 1513.1 98.3 (87.0, 111) AUC_(0-inf) (pg · hr/mL) 1670.7 1593.6 104.8 (93.4, 117.7) Treatment Evs G C_(max) (pg/mL) 803.2 728.4 110.3 (87.8, 138.5) 17 mg ER C_(max1)(pg/mL) 593.9 648.6 91.6 (81.4, 103.0) (10 mg IR 7 mg C_(max2) (pg/mL)566.6 595.8 95.1 (61.8, 146.4) DR 50% EC) C_(4 hr) (pg/mL) 160.0 20.9765.4 (410.2, 1428.1) vs Reference C_(8 hr) (pg/mL) 61.2 36.0 169.9(128.3, 225.1)  AUC₀₋₈ (pg · hr/mL) 1499.8 1417.5 105.8 (92.1, 121.6)AUC₀₋₄ (pg · hr/mL) 856.2 688.1 124.4 (108.9, 142.2)  AUC₄₋₈ (pg ·hr/mL) 573.4 702.9 81.6 (61.6, 108.0) AUC_(0-last) (pg · hr/mL) 1706.31513.1 112.8 (99.7, 127.5) AUC_(0-inf) (pg · hr/mL) 1962.7 1593.6 123.2(109.7, 138.3)  Treatment F vs G C_(max) (pg/mL) 759.6 728.4 104.3(83.0, 131.0) 15 mg ER C_(max1) (pg/mL) 657.4 648.6 101.4 (90.1, 114.0)(10 mg IR 5 mg C_(max2) (pg/mL) 364.8 595.8 61.2 (41.7, 89.9)  DR 60%EC) C_(4 hr) (pg/mL) 69.2 20.9 331.1 (177.4, 617.7)  vs ReferenceC_(8 hr) (pg/mL) 43.7 36.0 121.2 (91.5, 160.6) AUC₀₋₈ (pg · hr/mL)1191.1 1417.5 84.0 (73.1, 96.5)  AUC₀₋₄ (pg · hr/mL) 790.9 688.1 114.9(100.6, 131.3)  AUC₄₋₈ (pg · hr/mL) 360.4 702.9 51.3 (43.8, 60.0) AUC_(0-last) (pg · hr/mL) 1335.4 1513.1 88.3 (78.1, 99.8)  AUC_(0-inf)(pg · hr/mL) 1483.1 1593.6 93.1 (82.7, 104.7) ^(a)IR: immediate release;DR: delayed release; EC: enteric coating ^(b)Values displayed are LeastSquares Geometric Mean for all treatments (Test) relative to referenceTreatment G (i.e., 10 mg phenylephrine HCl administered q4h for 2sequential doses) ^(c)90% confidence interval (CI) for ratio of test toreference means (expressed as %)

The Example 2 study results demonstrated that Treatment D exhibited aratio of means and 90% CIs for overall AUC₀₋₈, AUC_(0-last), andAUC_(0-inf) that were contained within the 80% to 125% equivalence rangerelative to the reference Treatment G. The upper bound of the 90%confidence interval for C_(max) from Treatment D was found to bemarginally higher than the 125% upper bound relative to theimmediate-release treatment. However, the AUC₄₋₈ and C_(max2) did notexhibit a ratio of means and 90% CIs within the 80% to 125% equivalencerange and therefore Example D may not be bioequivalent, in particularwith respect to AUC₄₋₈ and C_(max2).

From statistical comparisons of other treatments relative to thereference Treatment G, it was determined that while Treatments B and Eexhibited point estimates (ratio of means) that were within the 80-125%equivalence range for several parameters, but they also displayed upperbounds of the 90% confidence interval that were higher than 125% fortheir respective C_(max) and AUC_(0-inf) values. Additionally, theAUC₄₋₈, and C_(max2) for Examples B and E did not exhibit a ratio ofmeans and 90% CIs within the 80% to 125% bioequivalence range andtherefore Examples B and E may not be bioequivalent, in particular withrespect to AUC₄₋₈ and C_(max2).

The Example 2 study results demonstrate that the AUC₄₋₈, and C_(max2)did not exhibit a ratio of means and 90% CIs within the 80% to 125%equivalence range for Treatments C and F and therefore Examples C and Fmay not be bioequivalent, in particular with respect to AUC₄₋₈, andC_(max2).

The Example 2 study results also demonstrate that the C_(max) did notexhibit a ratio of means and 90% CIs within the 80% to 125% equivalencerange for Treatment A and therefore Example A may not be bioequivalent,in particular with respect to C_(max).

Based on the results from Example 2, additional examples were made andtested with higher levels of PE in the ER portion in order to increasethe exposure in the 4 to 8 hour interval, including the AUC₄₋₈ andC_(max2), so the dosage form meets or exceeds the PK profile of twosequentially administered (every 4 hours) doses of a commerciallyavailable immediate release phenylephrine hydrochloride 10 mg referenceproduct.

Example 3

Treatments A-E were made and tested to determine whether higher doseextended-release phenylephrine hydrochloride treatments (total dosages≥20 mg) could provide systemic exposures to unconjugated phenylephrinethat met or exceeded the exposures from two sequentially administered(every 4 hours) doses of a commercially available immediate releasephenylephrine hydrochloride 10 mg reference product (Treatment F).Treatments A-E are summarized in Table 5, below. Treatments A-E arefurther described in Table 13 and Table 14, hereafter.

This study was conducted as a randomized, open-label, 6-treatment,4-period, incomplete crossover design single-dose study in a total of 30healthy subjects, with a washout of at least 7 days between dosing foreach treatment. The five treatments investigated (Treatments A-E)provided a total single dose of 20 to 40 mg phenylephrine hydrochloride(see Table 5).

Reference Treatment F was 2 Equate™ Suphedrine (immediate-releasephenylephrine HCl 10 mg) doses administered 4 hours apart. Equate™Suphedrine PE, was supplied to the test site as commercially availabletablets (Lot#5LE1574, manufactured by Perrigo® Company [Allegan, Mich.])with protocol specific labeling.

During confinement, subjects provided blood samples for PK analysis ofunconjugated phenylephrine levels at various time points, includingbefore dosing and up to 12 hours after dosing. Bioanalysis ofunconjugated phenylephrine in plasma was conducted using a LC/MS-MSmethod with a LLOQ of 10 pg/mL.

TABLE 5 Investigational Treatments for Example 3 DR Particles IRParticles Enteric Coating Example 3 Dose PE Level Dose PE Total dose PETreatment (mg) (wt %) (mg) (mg) A 10 45 10 20 B 10 45 15 25 C 10 45 2030 D 15 45 15 30 E* 20 45 20 40 *Example 3, Treatment E is two PE HClextended-release capsules for a total 40 mg dose (i.e. two capsules ofExample A). Treatments A-D are one capsule containing IR and DRportions.

Several pharmacokinetic parameters were evaluated to characterizesystemic exposures of unconjugated phenylephrine from theextended-release treatments relative to the immediate-release referencetreatment over an 8-hour exposure interval. Results, summarized in Table6, indicate that the bioavailability for unconjugated phenylephrine wassignificantly higher for all pharmacokinetic parameters relative to theimmediate-release reference treatment. Point estimates for percent ratioof means was ≥100%, and the lower bound of the 90% confidence intervalgreater than 80%, for most parameters for all five experimentaltreatments relative to the reference treatment.

TABLE 6 Pharmacokinetic Parameters and Statistical Comparisons forUnconjugated Phenylephrine T/R Ratio Test Reference of MeansComparison^(a) PK Parameter (T)^(b) (R)^(b) (%) 90% CI^(c) Treatment Avs F C_(max) (pg/mL) 1403.8 690.0 203.4 (146.2, 283.1) 20 mg ER C_(max1)(pg/mL) 598.0 668.7 89.4  (78.6, 101.8) (10 IR + 10 DR) C_(max2) (pg/mL)1028.2 587.5 175.0 (105.8, 289.6) vs Reference C_(4 hr) (pg/mL) 168.912.1 1400.7  (662.9, 2959.6) C_(8 hr) (pg/mL) 44.8 30.6 146.7 (110.3,195.2) AUC₀₋₄ (pg · hr/mL) 949.7 597.8 158.9 (124.3, 203.0) AUC₄₋₈ (pg ·hr/mL) 747.7 610.1 122.5  (88.7, 169.4) AUC_(0-last) (pg · hr/mL) 2444.01370.4 178.3 (154.3, 206.1) AUC_(0-inf) (pg · hr/mL) 2566.6 1433.2 179.1(156.3, 205.2) Treatment B vs F C_(max) (pg/mL) 1938.3 690.0 280.9(201.9, 390.9) 25 mg ER C_(max1) (pg/mL) 689.3 668.7 103.1  (90.6,117.3) (10 IR + 15 DR) C_(max2) (pg/mL) 1557.1 587.5 265.0 (160.2,438.5) vs Reference C_(4 hr) (pg/mL) 187.2 12.1 1552.5  (734.7, 3280.5)C_(8 hr) (pg/mL) 80.1 30.6 262.1 (197.0, 348.7) AUC₀₋₄ (pg · hr/mL)1046.8 597.8 175.1 (137.0, 223.8) AUC₄₋₈ (pg · hr/mL) 1151.6 610.1 188.7(125.8, 283.2) AUC_(0-last) (pg · hr/mL) 3339.2 1370.4 243.7 (210.8,281.6) AUC_(0-inf) (pg · hr/mL) 3535.1 1433.2 246.7 (215.2, 282.7)Treatment C vs F C_(max) (pg/mL) 3533.7 690.0 512.1 (368.0, 712.6) 30 mgER C_(max1) (pg/mL) 620.2 668.7 92.7  (81.5, 105.6) (10 IR + 20 DR)C_(max2) (pg/mL) 3027.2 587.5 515.3 (311.4, 852.5) vs Reference C_(4 hr)(pg/mL) 213.8 12.1 1772.5  (838.8, 3745.2) C_(8 hr) (pg/mL) 122.4 30.6400.6 (301.1, 523.9) AUC₀₋₄ (pg · hr/mL) 1211.7 597.8 202.7 (158.6,259.1) AUC₄₋₈ (pg · hr/mL) 2155.7 610.1 353.3 (227.5, 548.7)AUC_(0-last) (pg · hr/mL) 5551.2 1370.4 405.1 (350.5, 468.2) AUC_(0-inf)(pg · hr/mL) 5823.5 1433.2 406.3 (354.6, 465.6) Treatment D vs F C_(max)(pg/mL) 2342.8 690.0 339.5 (243.7, 473.0) 30 mg ER C_(max1) (pg/mL)1090.7 668.7 163.1 (143.2, 185.7) (15 IR + 15 DR) C_(max2) (pg/mL)1683.1 587.5 286.5 (172.8, 474.9) vs Reference C_(4 hr) (pg/mL) 259.812.1 2154.5 (1016.8, 4565.1) C_(8 hr) (pg/mL) 71.9 30.6 235.3 (176.7,313.4) AUC₀₋₄ (pg · hr/mL) 1658.1 597.8 277.4 (216.8, 354.8) AUC₄₋₈ (pg· hr/mL) 1316.4 610.1 215.8 (147.4, 315.7) AUC_(0-last) (pg · hr/mL)4230.5 1370.4 308.7 (266.9, 357.0) AUC_(0-inf) (pg · hr/mL) 4388.31433.2 306.2 (267.1, 351.1) Treatment E vs F C_(max) (pg/mL) 2487.1690.0 360.4 (259.0, 501.5) 40 mg ER C_(max1) (pg/mL) 1413.8 668.7 211.4(185.8, 240.6) (20 IR + 20 DR)^(d) C_(max2) (pg/mL) 1995.6 587.5 339.7(205.3, 562.0) vs Reference C_(4 hr) (pg/mL) 365.7 12.1 3032.7 (1435.3,6408.1) C_(8 hr) (pg/mL) 135.3 30.6 442.7 (332.7, 588.9) AUC₀₋₄ (pg ·hr/mL) 2142.0 597.8 358.3 (280.3, 457.9) AUC₄₋₈ (pg · hr/mL) 1761.9610.1 288.8 (217.2, 383.9) AUC_(0-last) (pg · hr/mL) 5667.7 1370.4 413.6(357.8, 478.0) AUC_(0-inf) (pg · hr/mL) 5959.1 1433.2 415.8 (362.8,476.5) ^(a)IR: immediate release; DR: delayed release; EC: entericcoating ^(b)Values displayed are Least Squares Geometric Mean for alltreatments (Test) relative to reference Treatment G (i.e., 10 mgphenylephrine HCl administered q4h for 2 sequential doses) ^(c)90%confidence interval (CI) for ratio of test to reference means (expressedas %) ^(d)Treatment E (40 mg ER) was dosed as 2 × 20 mg Treatment Acapsules (each capsule containing 10 IR + 10 DR) Statistical methodologynote: AUC₄₋₈ allows residual variance to vary by treatment group. Otherparameters use traditional constant variance assumptions

FIGS. 5A, B, and C show the mean unconjugated phenylephrineconcentration for Treatments A-E versus Reference Treatment F. Inparticular FIG. 5A shows A, B, and C versus Reference Treatment F, FIG.5B shows Treatments A, D, and E versus Reference Treatment F, and FIG.5C shows Treatment A versus Reference Treatment F. The pharmacokineticresults from Example 3 illustrate that Treatments A-E all deliveredphenylephrine exposures over the entire dosing interval, as well as overthe 0-4 hour and 4-8 hour intervals post dosing, meeting or exceedingthe corresponding exposures of the immediate-release reference, as notedfrom overall AUC(0-tlast), AUC(0-inf), AUC(0-4), and AUC(4-8).

Treatment A (20 mg extended-release phenylephrine hydrochloride) couldbe a preferred treatment, since it has the lowest dosageextended-release treatment providing an exposure profile that meets orexceeds the exposure profile of the reference product.

Safety variables, including blood pressure (BP), heart rate (pulse, HR),and ECG parameters were assessed for Treatments A-E vs. the control(Treatment F: Equate® Suphedrine PE, 10 mg phenylephrine hydrochlorideadministered q4h for 2 sequential doses). BP and HR variationspotentially associated with the study treatments after dosing werecompared to the reference treatment.

Overall, the study treatments all showed a similar safety profile: nosignificant changes in blood pressure, heart rate, or ECG parameterswere associated with any specific treatment. In summary, allinvestigational treatments were considered safe, and were well toleratedby the subjects participating in the study.

Example 4

The amount of phenylephrine released was calculated using an HPLC Assay,as described below. When the amount of phenylephrine released is greaterthan the acid limit, which is about 10%, this is the lag time. While notwishing to be bound by theory, it is believed that the Krebs buffer,which contains bicarbonate, is a better approximation for the conditionsin the digestive tract than other dissolution methods, which usephosphate buffers, and can lead to better approximations for delayedrelease particles.

FIG. 6 shows the amount of phenylephrine released, in vitro using theKrebs Buffer Dissolution Method, as described below, over time withdifferent formulation prototypes. The prototypes shown in FIG. 6 andTable 7, below, correspond to Treatments A-F. Treatments A-F are furtherdescribed in Table 11 and Table 12, hereafter.

TABLE 7 Amount % wt gain of pH Prototype lag time Delayed releasephenylephrine sensitive in Krebs Buffer particles (mg) coating (hours)Treatment C 3 50 2 Treatment A 5 40 1.5 Treatment D 5 50 2 Treatment F 560 2.4 Treatment B 7 40 1.5 Treatment E 7 50 2

In one example, the lag time as determined by following the Krebs BufferMethod is from about 0.5 hours to about 6 hours, in another example fromabout 1 hour to about 4 hours, in another example from about 1.25 hoursto about 3 hours, and in another example from about 1.5 hours to about2.5 hours.

In one example, the AUC, including the AUC₀₋₄, AUC₀₋₈, AUC₄₋₈,AUC_(0-inf), and/or AUC_(0-last), for a dosage form that can beadministered every eight hours can meet or exceed the AUC for two 10 mgimmediate release doses administered every four hours. In anotherexample, the AUC for a dosage form that can be administered every twelvehours can meet or exceed the AUC for three 10 mg immediate release dosesadministered every four hours. In such a dosage form, C_(max) for thenovel form can meet or exceed the immediate release form dosed every 4hours for a total of two or three doses.

In another example, the AUC for a dosage form that can be administeredevery eight hours can be substantially equivalent or greater than theAUC for two 10 mg immediate release doses administered every four hours.In another example, the AUC for a dosage form that can be administeredevery twelve hours can be substantially equivalent or greater than theAUC for three 10 mg immediate release doses administered every fourhours. In such a dosage form, C_(max) for the novel form can also besubstantially equivalent or greater than the immediate release formdosed every 4 hours for a total of two or three doses.

In another example, the dosage form can have a higher AUC and/or C_(max)for the immediate release particles and the delayed release particles ascompared to the AUC and/or C_(max) for 10 mg immediate release dosesadministered every four hours.

In order to provide delayed release phenylephrine dosage forms, thedosage form can be properly formulated.

The dosage form can contain a plurality of particles. The term particleis not meant to be limiting and can include microcrystals,micro-particles, beads, microbeads, powders, granules, pellets,micropellets, nonpareil seeds, and microcapsules. In one example theparticle is from about 200 μm to about 1500 μm in its longest dimension,in another example about 300 μm to about 1000 μm, in another exampleabout 400 μm to about 800 μm, and in another example about 500 μm toabout 725 μm. In another example, the particles can be about 700 μm toabout 925 μm in its longest diameter. In another example, the particlesare spherical or substantially spherical. In another example, the dosageform contains at least 100 delayed release particles, in another exampleat least 200 delayed release particles, in another example at least 300delayed release particles, in another example at least 400 delayedrelease particles, in another example at least 500 delayed releaseparticles, in another example at least 600 delayed release particles,and in another example at least 750 delayed release particles.

In another example, the delayed release particles can be substantiallysmooth. If the delayed release particles are not smooth, for instance ifthey are spiked or have a rough surface appearance, the dissolution canbe altered. If the particles are spiked or have a rough surface, therelease of phenylephrine can be early as the phenylephrine can leak outof the portions of the particles that have the thinnest coating level.In one example, the particles are substantially smooth, as visuallyperceived under a microscope with a total magnification of 40×. As usedherein, “visually perceived under a microscope” means that a humanviewer can visually discern that the particle is smooth and the surfacehas an appearance that is substantially similar to a particle without apH sensitive coating under a properly focused microscope with a totalmagnification of 40×. FIGS. 7 A, B, C and D show digital photographs ofparticles that are not substantially smooth as can be visually perceivedunder a microscope with a total magnification of 40×. FIGS. 8 A, B, C,and D show digital photographs of particles that are substantiallysmooth as can be visually perceived under a microscope with a totalmagnification of 40×. The substantially smooth particles can beout-of-round and still smooth.

In another example, smoothness can be determined by the Smoothness TestMethod, as described hereafter. In one example, the particles can have amean circularity from about 0.70 to about 1, in another example fromabout 0.75 to about 1, in another example from about 0.8 to about 1, inanother example from about 0.85 to about 1, in another example fromabout 0.90 to about 1, and in another example from about 0.95 toabout 1. In another example particles can have a mean circularity fromabout 0.72 to about 0.95, to about 0.78 to about 0.93, and from about0.82 to about 0.89.

In one example, the dosage form can deliver a therapeutic blood plasmaconcentration of unconjugated phenylephrine for at least 6 hours, inanother example for at least 8 hours, in another example for at least 10hours, and in another example for at least 12 hours.

The core of the particles in the present dose form can contain anypharmaceutically suitable material. Non-limiting examples of corematerials can consist of microcrystalline cellulose, sugars, starches,polymers, and combinations thereof. In one example, the core can bemicrocrystalline cellulose spheres marketed under the tradename“Cellets®” available from Glatt® Air Techniques Inc., Ramsey, N.J. Inone example, the microcrystalline cellulose spheres can have a diameterof about 500 μm to about 710 μm and a bulk density of about 0.7 g/cc toabout 0.9 g/cc. In one example, at least about 85% have a diameter ofabout 500 μm to about 710 μm.

The delayed release particles can contain a pH sensitive coating whichmeans that the coating dissolves when it is immersed in a particular pH,which can be basic or acidic. In one example the pH sensitive coating isan enteric coating. It can be important for the coating to be theappropriate thickness or appropriate weight percentage. If the coatingis too thin or the weight percentage is too low, then the phenylephrinecan be released too early relative and the lag time can be shorter thanrequired. One problem with releasing the phenylephrine too early is thatthe doses can be too close together and the user may not have asustained level of unconjugated phenylephrine for the intended duration.

If the coating is too thick or if the weight percentage is too high,then the phenylephrine can be released suboptimally with respect toachieving the intended 6-12 hour duration of dosing. If thephenylephrine is released too distally in the small intestine then theremay not be enough time for the phenylephrine to enter the blood streambefore entering the colon. While not wishing to be bound by theory, thecolon may not have enough liquid to allow the dissolution ofphenylephrine and a reduced surface area to allow for systemicabsorption. Therefore it can be advantageous for significant dissolutionof the dose form and active to occur prior to migration into the colon.

The weight percent (wt. %) increase of the particle after the pHsensitive coating is added can be from about a 30 wt. % to about a 60wt. % increase, in another example from about a 35 wt. % to about a 55wt. %, in another example from about a 37% to about a 53%, in anotherexample from about a 40 wt. % to about a 50 wt. %, and in anotherexample from about a 43% to about a 47%.

In another example, the wt. % increase of the particle after the pHsensitive coating is added can be from about a 35 wt. % to about a 70wt. % increase, from about a 40 wt. % to about a 65 wt. %, from about a42 wt. % to about a 60 wt. %, from about a 45 wt. % to about a 57 wt. %,and from about a 48 wt. % to about a 53 wt. %.

In another example, the wt. % increase of the particle after the pHsensitive coating is added can be from about a 15 wt. % to about a 65wt. % increase, in another example from about a 25 wt. % to about a 55wt. % increase, and in another example from about a 35 wt. % to about a45 wt. % increase.

In another example, the wt. % increase after the pH sensitive coating isadded can be from about a 25 wt. % to about a 75 wt. % increase, inanother example from about a 35 wt. % to about a 45 wt. % increase, andin another example from about a 45 wt. % to about a 55 wt. % increase.

In another example, the wt. % increase after the pH sensitive coating isadded can be from about a 40 wt. % to about a 80 wt. % increase, inanother example from about a 50 wt. % to about a 75 wt. % increase, andin another example from about a 55 wt. % to about a 65 wt. % increase.

In another example, the wt. % increase after the pH sensitive coating isadded is from 20 wt. % to about 60 wt. %, in another example from about30 wt. % to about 55 wt. %, in another example from about 40 wt. % toabout 50 wt. %, in another example from about 42 wt. % to about 48 wt.%, in another example from about 44 wt. % to about 46 wt. %, and inanother example about 45 wt. %. The wt. % increase after the pHsensitive coating is added is from about 10 wt. % to about 50 wt. %, inanother example from about 20 wt. % to about 45 wt. %, in anotherexample from about 30 wt. % to about 40 wt. %, in another example fromabout 32 wt. % to about 38 wt. %, in another example from about 34 wt. %to about 36 wt. %, and in another example about 35 wt. %. In anotherexample, the wt. % increase after the pH sensitive coating is added isfrom about 30 wt. % to about 50 wt. % and in another example from about35 wt. % to about 45 wt. %.

In another example, the delayed release particles can optionallycomprise from about a 5 wt. % to about a 55 wt. % pH sensitive coating,by weight of the particle, in another example from about a 10 wt. % toabout a 45 wt. %, and in another example from about a 15 wt. % to abouta 35 wt. %.

In another example, the pH sensitive coating is from about 10 μm toabout 200 μm thick, in another example from about 15 μm to about 150 μm,in another example from about 25 μm to about 125 μm, in another examplefrom about 30 μm to about 100 μm, in another example from about 40 μm toabout 80 μm, in another example from about 45 μm to about 75 μm, inanother example from about 50 μm to about 70 μm, in another example fromabout 55 μm to about 65 μm, and in another example from about 57 μm toabout 63 μm. In one example, the pH sensitive coating can be about 60 μmthick.

In another example, the delayed release particle contains one or morecoatings and the total thickness of the coatings is from about 20 μm toabout 300 μm thick, in another example from about 40 μm to about 200 μm,in another example from about 60 μm to about 175 μm, in another examplefrom about 70 μm to about 150 μm, in another example from about 75 μm toabout 125 μm, in another example from about 85 μm to about 115 μm, andin another example from about 90 μm to about 110 μm. In one example theone or more coatings can be about 100 μm thick.

The pH sensitive coating can be an enteric coating. In one example, thepH sensitive coating can be degradable in the small intestine at a pH ofat least 5.5 and in another example the pH coating can be degradablewhen the pH is at least 7.0. In another example, the pH sensitivecoating can be degradable at a pH from about 5-9, in another exampleabout 6-8, and in another example from about 6.5-7.5. In any event, inone example, the pH sensitive coating can avoid degradation prematurephenylephrine dissolution in the low pH in the stomach.

The pH sensitive coating can contain one or more polymers alone or incombination with water soluble or insoluble polymers. The pH sensitivecoating can contain any chemically stable, biocompatible polymer. In oneexample, the pH sensitive coating has a weight average molecular weightof from 100,000 g/mol to 600,000 g/mol, in another example 150,000 g/molto 500,000 g/mol, in another example 200,000 g/mol to 400,000 g/mol, inanother example 225,000 g/mol to 350,000 g/mol, and in another example250,000 g/mol to 300,000 g/mol.

Non-limiting examples of polymers can include cellulose esters andderivatives, acrylate copolymers, hypromellose acetate succinate,polyvinyl acetates and derivatives (commercially available asKollicoat®, from BASF, Tarrytown, N.J.), shellac, and combinationsthereof.

Non-limiting examples of cellulose esters and derivatives can includecellulose acetate phthalate, hydroxypropyl methylcellulose phthalate(HPMCP), hydroxypropyl methylcellulose acetate succinate, celluloseacetate tetrahydrophthalate, cellulose acetate hexahydrophthalate,hydroxypropyl cellulose acetate succinate, and combinations thereof.

Non-limiting examples of acrylate copolymers can includemethyl-methacrylate esters copolymerized with methacrylic acid, acrylicacid and esters copolymerized with methacrylic acid and esters,ammonio-containing acrylate copolymers, and combinations thereof.

In one example, the polymer can be an anionic copolymer based on methylacrylate, methyl methacrylate, and methacrylic acid. In one example, thecoating can contain Poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) 7:3:1 polymer marketed under thetradename “Eudragit® FS30D”, available from Evonik Industries,Darmstadt, Germany. In another example, the coating can further comprisePoly(methacrylic acid-co-ethyl acrylate) 1:1 polymer, marketed under thetradename “Eudragit® L30D”, commercially available from Evonik,Darmstadt, Germany.

In one example, the pH sensitive coating can contain both Eudragit®FS30D and Eudragit® L30D. In one example, the pH sensitive coating cancontain from 50% to 95% FS30D, by weight of the total Eudragit®, inanother example 60% to 90%, and in another example 70% to 85%. In oneexample, the pH sensitive coating can contain 85% FS30D and 15% L30D byweight of the Eudragit®, in another example the pH sensitive coating cancontain 90% FS30D and 10% L30D, and in another example the pH sensitivecoating can contain 100% FS30D.

In one example, the pH sensitive coating can contain more than onepolymer that can be mixed at any ratio to control where thephenylephrine is released.

In one example, the immediate release particles can have a polymercoating, which is not an enteric coating and can dissolve upon enteringthe stomach.

In another example, the % of phenylephrine in the dosage form and/or theimmediate release dosage forms and/or the delayed release particles cancontain from about 2% to about 20%, in another example from about 5% toabout 15%, in another example from about 7% to about 12%, in anotherexample from about 8% to about 10%, and in another example from about 7%to about 9%. In another example, the % of phenylephrine in the dosageform and/or the immediate release dosage forms and/or the delayedrelease particles can be greater than about 5%, in another examplegreater than about 6%, in another example greater than about 7%, inanother example greater than about 8%, in another example greater thanabout 9%, in another example greater than about 10%, in another examplegreater than about 11%, and in another example greater than about 12%.In another example, the % of phenylephrine in the dosage form and/or theimmediate release dosage forms and/or the delayed release particles canbe less than about 25%, in another example less than about 20%, inanother example less than about 15%, in another example less than about12%, and in another example less than about 10%. In another example, the% of phenylephrine in the dosage form and/or the immediate releasedosage forms and/or the delayed release particles can be from about 8%to about 30%, in another example from about 10% to about 25%, in anotherexample from about 12% to about 20%, and in another example from about13% to about 18%. In another example, the % of phenylephrine in thedosage form and/or the immediate release dosage forms and/or the delayedrelease particles can be from about 10% to 75%, in another example from20% to 50%, and in another example from 30% to 40%.

The ratio of immediate release particles or other immediate releaseforms to delayed release particles can vary. In one example, eachimmediate release form can contain the same amount of phenylephrine aseach delayed release particle and the ratio of immediate release form todelayed release particle can be adjusted to achieve the desired dose andeffect. In another example, the ratio of the amount of phenylephrinewith the immediate release forms to the amount of phenylephrine coatedon the delayed release particles can be greater than about 1:1. Inanother example, the ratio of the amount of phenylephrine with theimmediate release forms to the amount of phenylephrine coated on thedelayed release particles can be less than about 1:1. And in anotherexample, the ratio of the amount of phenylephrine with the immediaterelease forms to the amount of phenylephrine on the delayed releaseparticles can be equal to about 1:1. In one example, the ratio of theamount of phenylephrine with the immediate release forms to the amountof phenylephrine coated on the delayed release particles can be fromabout 1:4 to about 4:1, in another example from about 1:3 to about 3:1,and in another example from about 1:2 to about 2:1. In another example,the ratio of the amount of phenylephrine with the immediate releaseforms to the amount of phenylephrine on the delayed release particlescan be from 1:1 to 1:5, in another example from 1:1.5 to 1:4, in anotherexample from 1:2 to 1:3, and in another example from 1:2.5 to 1:2.75. Inanother example, the ratio of the amount of phenylephrine with theimmediate release forms to the amount of phenylephrine coated on delayedrelease particles can be greater than about 1:5, in another examplegreater than about 1:4, in another example greater than about 1:3, inanother example greater than about 1:2 and in another example greaterthan about 1:1. If the ratio is not optimal, then the product may notachieve the desired dosing regimen, e.g. once every 6-12 hours.

In another example, the amount of phenylephrine on each immediaterelease particle or other immediate release forms can be different thanthe amount of phenylephrine on each delayed release particle. In anotherexample, the immediate release particles or other immediate release formcan contain more phenylephrine than the delayed release particles andthe amount of phenylephrine is adjusted via the amount coated onto eachparticle. In another example, the immediate release particles or otherimmediate release forms can contain less phenylephrine than the delayedrelease particles and the amount of phenylephrine is adjusted via theamount coated onto each particle. In another example, the immediaterelease particles or other immediate release form can containapproximately the same amount of phenylephrine as the delayed releaseparticles.

The ratio of immediate release particles or other immediate release formto delayed release particles can be adjusted depending on the desired PKprofile. In one example, the PK profile can be substantially equivalentto an immediate release dose form administered every four hours. Inanother example, the PK profile is greater than the PK profile ofmultiple immediate release dose forms administered every four hours andis considered safe and effective for an OTC decongestion product. Inanother example, the PK profile is not substantially equivalent to a thePK profile of multiple immediate release dose forms administered everyfour hours but is considered to be safe and effective for an OTCdecongestion product.

In one example, the multi-particle dosage form can have two pulses, canbe administered every eight hours, and can be substantially equivalentto the PK profile for two four hour doses of a commercially availablephenylephrine product. In another example, the multi-particle dosageform can have two pulses, can be administered every eight hours, and canhave a minimum PK profile that is substantially bioequivalent to the PKprofile for two four hour doses of a commercially availablephenylephrine product. In another example, the multi-particle dose formcan contain both immediate and delayed release phenylephrine particlesand can be administered every 6-8 hours and can have a PK profile thatsubstantially surpasses the PK profile phenylephrine from commerciallyavailable phenylephrine product dosed every 4 hours. In one example theimmediate release particles or other immediate release form and thedelayed release particles can have the same amount of phenylephrine, theweight ratio of immediate release particles to delayed release particlescan be from about 1:1 to about 10:1, in another example the weight ratiocan range from about 1:1 to about 4:1.

In one example, a dose can contains both IR and DR forms and the dosecan contain from about 5 mg to about 100 mg phenylephrine hydrochloride,in another example from about 10 mg to about 75 mg, in another examplefrom about 15 mg to about 60 mg, and in another example from about 20 mgto about 50 mg. In another example, a dose can contain from about 5 mgto about 40 mg phenylephrine hydrochloride, in another example fromabout 7 mg to about 30 mg, in another example from about 10 mg to about25 mg, and in another example from about 10 mg to about 20 mg. In oneexample, a dose can contain 20 mg phenylephrine hydrochloride.

In one example, the dosage form can contain at least an immediaterelease form, for instance, immediate release particles, powders,granules, beads. In one example, the immediate release form can be aliquid. In another example the immediate release form can be a solid. Inanother example the dosage form can contain a plurality of immediaterelease forms and in another example the dosage form can contain acouple of immediate release dosage forms and in another example thedosage form can contain a single immediate release dosage form. In eachdose, the immediate release form can contain from about 3 mg to about 20mg phenylephrine hydrochloride, in another example from about 5 mg toabout 15 mg, in another example from about 7 mg to about 12 mg, and inanother example from about 9 mg to about 11 mg. In one example, a dosecan contain 10 mg phenylephrine hydrochloride in the immediate releaseform.

The dosage form can contain at least a delayed release form, inparticular, delayed release particles. The delayed release particles canhave a coating that contains phenylephrine hydrochloride and the coatingcan substantially surround a core. In one example, the core issubstantially free or free of phenylephrine. In another example, thecore is not seeded with phenylephrine, where seeded means that thephenylephrine is dispersed throughout the core.

In another example, the dosage form can contain at least a delayedrelease form and each dose can contain phenylephrine hydrochloride, inone example the dose can contain from about 5 mg to about 40 mg PE inthe delayed release form, in another example from about 7 mg to about 35mg, and in another example from about 10 mg to about 30 mg. In anotherexample, a dose of the delayed release form can contain from about 5 mgto about 20 mg phenylephrine hydrochloride, in another example fromabout 7 mg to about 15 mg, and in another example about 10 mg. Inanother example, a dose of the delayed release form can contain fromabout 10 to about 30 mg phenylephrine hydrochloride, in another exampleabout 15 mg to about 25 mg, and in another example about 20 mg. Inanother example, a dose of the delayed release form can contain fromabout 3 mg to about 9 mg phenylephrine, in another example from about 5mg to about 8 mg, and in another example about 7 mg.

In another example the dosage form can contain a delayed release formthat can contain less phenylephrine than the immediate release particlesor other immediate release forms. In another example, a dose of thedelayed release particles can contain less than about 20 mg ofphenylephrine, in another example less than about 15 mg phenylephrine,and in another example less than about 10 mg phenylephrine. In anotherexample a dose of the delayed release form can contain from about 2 mgto about 9 mg phenylephrine, in another example from about 3 mg to about7 mg phenylephrine, and in another example from about 4 mg to about 6 mgof phenylephrine. In another example, a dose of the delayed release formcan contain from about 1 mg to about 5 mg phenylephrine, in anotherexample from about 2 mg to about 4 mg, and in another example about 3mg. In another example, a dose of the delayed release form can containfrom about 2 to about 7 mg phenylephrine, in another example about 3 mgto about 6 mg, and in another example about 5 mg. In another example, adose of the delayed release form can contain from about 3 mg to about 9mg phenylephrine, in another example from about 5 mg to about 8 mg, andin another example about 7 mg.

In another example, the parameters including C_(max), C_(max1),C_(max2), C_(4hr), C_(8hr), AUC₀₋₄, AUC₄₋₈, AUC_(0-last), and/orAUC_(0-inf), for the pulsatile dosage form can meet or exceed systemicexposures relative to a commercially available, immediate release PEdose taken at 4 hour intervals while remaining safe and effective. Inone example, the ratio of means for pulsatile PE dosage form relative tothe IR treatment of one or more parameters can be at least about 85%, atleast about 90%, at least about 95%, at least about 100%, at least about110%, at least about 120%, at least about 130%, at least about 135%, atleast about 140%, at least about 145%, at least about 150%, at leastabout 155%, at least about 165%, at least about 170%, at least about175%, and at least 200%. In one example, the lower bound of the 90%confidence interval of one or more parameters for ratio of means forpulsatile PE dose relative to the IR treatment can be at least about75%, at least about 80%, at least about 85%, at least about 90%, atleast about 95%, at least about 97%, and at least about 100%. In anotherexample, the mean AUC₀₋₄ and/or the mean AUC₄₋₈ of the extended releasedosage form can be substantially equivalent and/or meets or exceeds themean AUC₀₋₄ and the mean AUC₄₋₈ of the reference formula (two 10 mgimmediate release PE doses administered every four hours).

In another example, the mean C_(max2) of the pulsatile dosage form isgreater than the mean C_(max1) of the pulsatile dosage form. In anotherexample, the ratio of the mean C_(max2) of the pulsatile dosage form tothe mean C_(max1) of the pulsatile dosage form is greater about 125%, inanother example greater than 150%, in another example greater than 165%,in another example greater than about 170%, in another example greaterthan 200%, in another example greater than 225%, in another examplegreater than 300%, and in another example greater than 600%. In theratio of the mean C_(max2) to the mean C_(max1) is from 90% to 300%, inanother example from about 100% to about 250%, in another example fromabout 125% to about 225%, in another example from about 150% to about200%, and in another example from about 160% to about 180%.

In one example, the mean C_(4hr) for the pulsatile dosage form can meetor exceed the mean C_(4hr) of the systemic exposures relative to an IRreference formula (commercially available, immediate release PE dosetaken at 4 hour intervals) while remaining safe and effective. In oneexample, the mean C_(4hr) for the pulsatile dosage form can be at leasttwo-fold greater than the mean C_(4hr) of the systemic exposuresrelative to a reference formula, in another example at least four-foldgreater, in another example at least eight-fold greater, and in anotherexample at least ten-fold greater. In another example, the upper boundof the 90% confidence interval for ratio of means for pulsatile PEdosage form relative to the IR treatment of the C_(4hr) can be at leastabout 90%, at least about 100%, at least about 150%, at least about200%, at least about 250%, at least about 500%, at least about 1000%, atleast about 1250%, at least about 1500%, at least about 2000%, and atleast about 2500%. In one example, the lower bound of the 90% confidenceinterval of the Can for ratio of means for pulsatile PE dose relative tothe IR treatment can be at least about 90%, at least about 100%, atleast about 150%, at least about 250%, at least about 300%, at leastabout 400%, and at least about 500%.

In one example, the mean C_(8hr), for the pulsatile dosage form can meetor exceed the mean C_(8hr) of the systemic exposures relative to an IRreference formula. In one example the mean C_(8hr) for the pulsatiledosage form is from about 100% to about 400% of the mean C_(8hr) of anIR reference formula, in another example from about 110% to about 200%,in another example from about 120% to about 175%, in another examplefrom about 130% to about 160%, and in another example from about 140% toabout 150%. In another example, the mean C_(8hr) for the pulsatiledosage form is at least about 90% of the mean C_(8hr) of an IR referenceformula, in another example at least about 100%, in another example atleast about 105%, in another example at least about 110%, in anotherexample at least about 115%, in another example at least about 120%, inanother example at least about 125%, in another example at least about130%, in another example at least about 135%, in another example atleast about 140%, and in another example at least about 145%.

In one example, the mean C_(4hr) for the pulsatile dosage form can meetor exceed the mean C_(8hr) for the pulsatile dosage. In another example,the mean C_(max2) for the pulsatile dosage form can meet or exceed themean C_(max1) for the pulsatile dosage form.

In another example, the mean C_(4hr) for the pulsatile dosage form isless than the mean C_(max1) for the pulsatile dosage form, for instancethe mean C_(4hr) can be at least from about 10% to about 50% of the meanC_(max1), from about 15% to about 45%, from about 20% to about 40%, fromabout 25% to about 35%, from about 27% to about 30%. In another example,C_(4hr) is less than about 50% of C_(max1), less than about 42%, lessthan about 40%, less than about 38%, less than about 35%, less thanabout 32%, less than about 30%.

In another example, mean C_(8hr) for the pulsatile dosage form is lessthan the mean C_(max2) for the pulsatile dosage form, for instance themean C_(4hr) can be at least from about 1% to about 20% of the meanC_(max1), from about 2% to about 15%, from about 3% to about 10%, andfrom about 4% to about 7%. In another example, the mean C_(8hr) for thepulsatile dosage form is less than about 12% of the mean C_(max2) forthe pulsatile dosage form, less than about 8%, less than about 7%, lessthan about 6%, and less than about 5%.

In another example, the mean AUC₄₋₈ for the pulsatile dosage form is atleast about 60% of the mean AUC₀₋₄ for the pulsatile dosage form, atleast about 65%, at least about 70%, at least about 72%, at least about75%, at least about 77%, at least about 85%, at least about 90%, atleast about 95%, at least about 100%, at least about 125%, and at leastabout 150%. In another example, the mean AUC₄₋₈ for the pulsatile dosageform is from about 55% to about 100% of the mean AUC₀₋₄ for thepulsatile dosage form, from about 60% to about 95%, from about 65% toabout 88%, from about 68% to about 86%, from about 74% to about 81%, andfrom about 76% to about 80%.

In another example the pulsatile dosage form achieves a mean t_(max2)(the time it takes to reach C_(max2)) in about 3 hours to about 7 hours,in about 3.5 hours to about 6.8 hours, in about 3.7 hours to about 6.5hours, in about 4 hours to about 6 hours, and in about 4.5 hours toabout 5.5. hours.

In one example, the delayed release form and the immediate release formcan contain about the same amount of phenylephrine. In another example,the delayed release form can contain more phenylephrine than theimmediate release form. In another example, the delayed release form cancontain less phenylephrine than the immediate release form.

As used herein, exceeds bioequivalence limits may include significantincreases in one or more pharmacokinetic parameters including C_(max)and/or AUC of unconjugated phenylephrine. For example, exceedsbioequivalence limits can include a greater than 2 fold increase inC_(max) and/or AUC of unconjugated phenylephrine, in another example agreater than 3 fold increase, in another example a greater than 4 foldincrease, in another example a greater than 5 fold increase, in anotherexample a greater than 6 fold increase, in another example a greaterthan 7 fold increase, in another example a greater than 8 fold increase,in another example a greater than 9 fold increase, and in anotherexample a greater than 10 fold increase. In one example, dosage formsthat exceed bioequivalence limits can be safe and efficacious.

The dosage form can contain an immediate release dose in any form. Inone example the immediate release dose can be coated on immediaterelease particles. In another example, the immediate release dose is notan immediate release particle. In another example, the immediate releasedose can be in a liquid. In another example the immediate release dosecan be a liquid and the delayed release particles are suspended in theliquid. In another example, the immediate release dose can be acombination of forms.

In another example, the immediate release dose can be a separate dosageform, for instance a tablet or a liquid and in one example the immediaterelease dose form is separate and taken concurrently with the extendedrelease particles.

In another example, the immediate release dose can be a granule and/orpowder that contains the active and optionally excipients for stabilityand processing. In the immediate release granules and/or powders, theactives and excipients can be dispersed, possibly approximately evenlydispersed, throughout the granules and/or powders. In one example, thegranules and/or powder do not contain a coating. In another example, thegranules and/or powder do not contain an active coating. In anotherexample the granules and/or powder contain an active coating containingphenylephrine.

The dosage form can contain immediate release particles or otherimmediate release forms comprising phenylephrine or salts thereof anddelayed release particles comprising phenylephrine or salts thereof. Anypharmaceutically acceptable salt of phenylephrine can be administered.Non-limiting examples of phenylephrine or salts thereof can includephenylephrine hydrochloride, phenylephrine bitartrate, phenylephrinetannate, and combinations thereof. In one example, the dosage form cancontain phenylephrine hydrochloride.

In addition to comprising phenylephrine, the dosage forms can containone or more drug actives in addition to phenylephrine. In one example,the drug actives can be immediate release drug actives, extended releasedrug actives, and/or delayed release drug actives. In one example, theadditional drug active can be formulated as particles.

In one example, the dosage form can be orally administered to a human totemporarily relieve sinus congestion and pressure and/or temporarilyrelieve nasal congestion due to the common cold, hay fever or otherupper respiratory allergies. In one example, the human can be an adultsand children 12 years and older. In one example, the human can be anadults and children 16 years and older. In one example, the human can bean adult 18 years and older. In another example, the human can be achild 4 to under 12 years.

In another example, one dose can be administered every eight hours, upto three times per day. In one example, the dosage form can beadministered every six hours, in another example every seven hours, inanother example every eight hours, in another example every nine hours,in another example every ten hours, and in another example every twelvehours. In one example, the dose can be administered up to four times perday, in another example up to three times per day, in another example upto two times per day, and in another example once per day. In oneexample, the dosage form can be administered once or twice and adifferent dosage form can be administered at bedtime.

The dosage forms can be considered safe and can have safety variables,including blood pressure, heart rate, and/or ECG parameterssubstantially similar or similar to a two sequential doses of immediaterelease phenylephrine taken four hours apart.

In one example, the additional drug active is a multi-symptom relief(MSR) cold/flu active which can be used to treat one or more cold/flusymptoms. MSR cold/flu actives can be used to treat a variety ofcold/flu symptoms including nasal congestion, runny nose, sneezing,headache, dry cough, sore throat, sinus pressure or pain, chestcongestion, muscle aches/pains, wet/chesty cough, fever, andcombinations thereof. MSR cold/flu actives can include decongestants,expectorants, antihistamines, antitussives, pain relievers, andcombinations thereof.

Non-limiting examples of expectorants can include guaifenesin, ambroxol,bromhexine, and combinations thereof.

Non-limiting examples of antihistamines can include chlorpheniramine,desloratadine, levocetirizine, diphenhydramine, doxylamine,triprolidine, clemastine, pheniramine, brompheniramine,dexbrompheniramine, loratadine, cetirizine and fexofenadine, amlexanox,alkylamine derivatives, cromolyn, acrivastine, ibudilast, bamipine,ketotifen, nedocromil, omalizumab, dimethindene, oxatomide, pemirolast,pyrrobutamine, pentigetide, thenaldine, picumast, tolpropamine,ramatroban, repirinast, suplatast tosylate aminoalkylethers, tazanolast,bromodiphenhydramine, tranilast, carbinoxamine, traxanox,chlorphenoxamine, diphenylpyaline, embramine, p-methyldiphenhydramine,moxastine, orphenadrine, phenyltoloxamine, setastine, ethylenediaminederivatives, chloropyramine, chlorothen, methapyrilene, pyrilamine,talastine, thenyldiamine, thonzylamine hydrochloride, tripelennamine,piperazines, chlorcyclizine, clocinizine, homochlorcyclizine,hydroxyzine, tricyclics, phenothiazines, mequitazine, promethazine,thiazinamium methylsulfate, azatadine, cyproheptadine, deptropine,desloratadine, isothipendyl, olopatadine, rupatadine, antazoline,astemizole, azelastine, bepotastine, clemizole, ebastine, emedastine,epinastine, levocabastine, mebhydroline, mizolastine, phenindamine,terfenadine, tritoqualine, and combinations thereof.

Non-limiting examples of antitussives can include dextromethorphan,menthol, codeine, chlophedianol, levodropropizine, and combinationsthereof.

Non-limiting examples of pain relievers can include acetaminophen,ibuprofen, ketoprofen, diclofenac, naproxen and salts thereof, aspirin,and combinations thereof.

In one example, the expectorant can be guaifenesin and in one examplethe dosage form can contain 200 mg of guaifenesin. In one example, theantihistamine can be chlorpheniramine and in one example the dosage formcan contain 125 mg of chlorpheniramine. In one example the antitussivecan be selected from the group consisting of dextromethorphan,chlophedianol, and combinations thereof. In one example the dosage formcan contains 10 mg of dextromethorphan and in another example the dosageform can contain 12.5 mg chlophedianol. In one example the painrelievers can include acetaminophen, ibuprofen, naproxen, orcombinations thereof. In one example the dosage form can contain 325 mgto 500 mg acetaminophen, in another example 200 mg ibuprofen, in anotherexample, 200 mg naproxen, and in another example 220 mg naproxen sodium.In one example, the cold/flu dosage unit can further comprise astimulant such as caffeine.

In one example, the dosage units can contain one or more MSR cold/fluactives, in another example two or more MSR cold/flu actives, in anotherexample three or more MSR cold/flu actives, and in another example fouror more MSR cold/flu actives. In one example, the dosage unit cancontain exactly one MSR cold/flu active, in another example exactly twoMSR cold/flu actives, in another example exactly three MSR cold/fluactives, and in another example exactly four MSR cold/flu actives. Inone example the dosage units can contain acetaminophen, dextromethorpan,and phenylephrine. In another example the dosage units can containnaproxen and/or naproxen sodium, dextromethorpan, and phenylephrine.

Krebs Buffer Dissolution Method

The Krebs Buffer Dissolution Method can be used to approximate therelease rate of phenylephrine in the digestive tract, in vitro. Testingis performed using the Type II (paddles) dissolution apparatus, asdescribed in USP <711> (Dec. 1, 2013).

Assemble the apparatus then place 500 mL of 0.1N HCl into each of 6vessels. Cover the vessels and allow the medium to equilibrate to atemperature of 37±0.5° C. Place one gelatin capsule containing delayedrelease particles into each vessel and commence dissolution testing.Operate the paddle speed at 50 revolutions per minute (RPM) for twohours. Stainless steel, spring style capsule sinkers that are 23 mm longby 8 mm wide (commercially available as Sotax style sinker, part #CAPWST-23 from QLA, Telford, Pa.) are used to prevent the capsules fromfloating in the vessels.

After two hours of dissolution in 0.1N HCl, withdraw a 10 mL aliquot ofsample from each vessel using separate 10 cc syringes connected tostainless steel cannulae with attached 10 μm filters (available fromQLA). Transfer each filtered acid phase sample into separate HPLC vialsfor analysis.

Then proceed immediately to the Krebs Buffer Stage of dissolutiontesting. This portion of the method requires a complete media exchange.Carefully transfer the undissolved particles and sinkers from each acidphase vessel to an apparatus containing 1000 mL pH 7.4 Krebs buffermedia into each of six vessels. Table 8, below, shows the composition ofKrebs buffer. The Krebs buffer is prepared fresh at time of use. The pHof the media in each vessel is adjusted to 7.40±0.05 prior to startingthe test using a sparging cannulae connected to a supply of carbondioxide gas. This gas is sparged directly into the vessels to lower thepH to the target value. The buffer should also be equilibrated to37±0.5° C. prior to starting the test. Throughout the entire test, gasis sparged into the vessels as needed at low pressure to maintain the pHwithin 7.40±0.05. The pH level inside the vessel is monitored by aportable pH meter.

TABLE 8 Millimolar Buffer Component (mM) Grams per liter Sodium chloride118.07 6.900 Potassium chloride 4.69 0.350 Magnesium sulfate 1.18 0.142Calcium chloride dihydrate 2.52 0.370 Potassium phosphate 1.18 0.161Sodium bicarbonate 24.00 2.016

The apparatus is operated at 50 RPM for up to eight hours. A 10 mLaliquot of sample is removed at appropriate intervals (e.g. every 30minutes) with a separate 10 cc syringe connected to a stainless steelcannula with attached 10 μm filter (available from QLA).

Then use the HPLC-UV Assay, as described herein, is used to determinethe percent dissolved values of phenylephrine in each sample aliquot.

HPLC Dissolution Assay

This method is applicable for the determination of phenylephrine insample aliquots from the Krebs Buffer Dissolution Method. The samplesare analyzed by HPLC with UV detection. The HPLC column is an AgilentZorbax Rapid Resolution, Catalog # HP863953-902, SB-C18, 3.5 μm, 4.6×150mm.

First, the stock and working standard solutions are prepared. Thesesolutions should be prepared fresh at time of use.

Standard Solution Preparation

Stock Solution (0.2 mg/mL)

Weigh 40.00±2 mg of Phenylephrine Reference Standard and transfer to a200 mL volumetric flask. Add approximately 20 mL of water and gentlyswirl, or sonicate if necessary, to dissolve. Dilute to volume withwater and mix well.

Acid Working Standard Solution (0.004 mg/mL)

Dilute stock solution 1:50 by adding 2 mL of stock solution into a 100mL volumetric flask, and bringing to volume with 0.1N HCl aciddissolution media. Mix well.

pH 7.4 Working Standard Solution (0.01 mg/mL)

Dilute stock solution 1:20 by adding 5 mL of stock into a 100 mLvolumetric flask, and bringing to volume with pH 7.4 Krebs buffer media.Mix well.

Set up the HPLC system as per the Chromatic Conditions, in Table 9,below.

TABLE 9 Time % A % B Gradient Conditions (min) (0.1% TFA) (Acetonitrile)0.0 96 4 3.5 96 4 3.6 50 50 4.5 50 50 4.6 96 4 7.0 96 4 Run Time: 7minutes Linear Gradient Column Temperature (° C.) 40 Sample compartmenttemperature Ambient Flow Rate (mL/min) 1.5 Detector Wavelength (nm) 275Injection volume (μL) 50

When the baseline stabilizes, inject at least one 0.1N HCl blank,followed by at least one injection of the 0.1N HCl working standardsolution to equilibrate the system.

Once the system is equilibrated, make 5 injections of the acid workingstandard solution and evaluate System Suitability Requirements 1-3,below.

Next, inject the acid-phase samples. Inject a bracketing standard atleast after every sixth acid-phase sample and after the last acid-phasesample. Evaluate System Suitability Requirement 4, below, for allacid-phase bracketing standard injections made throughout the run. Usethe overall average peak area from all acid standard injections madethroughout the run to calculate the acid-phase sample results.

After completing the acid-phase sample analysis, continue on to run thebuffer-phase analyses. As with the acid-phase analysis, eachbuffer-phase analysis must be performed with discrete quantitationagainst the respective pH-matched blank and standards. Begin with atleast one injection of the buffer blank solution (pH 7.4 Krebs Bufferdissolution media). Next, make 5 injections of the corresponding pH 7.4working standard solution followed by the respective sample injections.Make a bracketing buffer standard injection at least every sixth andafter the last respective buffer sample. Evaluate System SuitabilityCriteria 4 for all buffer-phase bracketing standard injections madethroughout the run. Then, the average peak area for all for all bufferstandard injections is calculated and used in the equations below tocalculate the sample results.

System suitability may be calculated after the chromatographic sequencehas been run. If the system suitability results fail to meetRequirements 1-3 for the acid working standard solution, then all data(acid and Krebs buffer) must be rejected and the sequence repeated. If abracketing standard fails to meeting Requirement 4, then thecorresponding samples bracketed by that standard must be rejected andthe analysis repeated.

System Suitability Requirements

-   -   1. Peak Tailing Factor—the tailing factor must be 2.0 or less        for the first acceptable acid standard injection.    -   2. Peak Area Repeatability—The Relative Standard Deviation (RSD)        for the peak area responses must be 2% or less for the first        five acceptable acid standard injections.    -   3. Peak Retention Time Repeatability—The RSD for the peak        retention times must be 2% or less for the first five acceptable        acid standard injections.    -   4. Overall Standard Peak Area Repeatability—The overall % RSD of        the peak areas for all standard injections made throughout the        run (5 initial injections plus bracketing standards) must be 2%        or less.

Calculations

${\%\mspace{14mu}{Dissolved}\mspace{14mu}\left( {{Acid} - {Phase}} \right)} = {\frac{{Peak}\mspace{14mu}{Area}\mspace{14mu}{Sample}}{{Avg}\mspace{14mu}{Peak}\mspace{14mu}{Area}\mspace{14mu}{Working}\mspace{14mu}{Std}} \times {Acid}\mspace{14mu}{Working}\mspace{14mu}{Std}\mspace{14mu}{Conc}\;\left( \frac{mg}{mL} \right) \times \frac{500\mspace{14mu}{mL}}{{Dose}\mspace{14mu}{Strength}\;({mg})} \times 100}$${\%\mspace{14mu}{Dissolved}\mspace{14mu}\left( {{Buffer} - {Phase}} \right)} = {\frac{{Peak}\mspace{14mu}{Area}\mspace{14mu}{Sample}}{{Avg}\mspace{14mu}{Peak}\mspace{14mu}{Area}\mspace{14mu}{Working}\mspace{14mu}{Std}} \times {Buffer}\mspace{14mu}{Working}\mspace{14mu}{Std}\mspace{14mu}{Conc}\;\left( \frac{mg}{mL} \right) \times \frac{1000\mspace{14mu}{mL}}{{Dose}\mspace{14mu}{Strength}\;({mg})} \times 100}$

If active is released during the acid phase, the pH 7.4 buffer phase %dissolved value needs to be corrected to account for active loss duringthe media exchange. The acid phase portion of the test (sample taken at2 hours) should have little to no active release. The % dissolved valueshould be zero. If it is not, then this value needs to be added to allbuffer phase results.

Smoothness Test Method

The Smoothness Test Method can be used to determine the circularity ofthe particles. Circularity is determined by (4π×([Area])/([Perimeter]²)and ranges from 0 (infinitely elongated polygon) to 1 (perfect circle).Thus, a particle with a rough, coarse, or spiked appearance can have alarger perimeter value as compared to a smooth particle with the samearea. Therefore, differences in surface topology can be calculated usingthe differences in the obtained circularity results.

Using a microscope (Nikon OPTIPHOT-2) and 40× magnification (4×magnifier and 10× eyepiece) and a digital camera (OptixCam SummitOCS-10.0) designed for microscopy, select the field of view thatcontains the particles to be analyzed. There should be spaces betweenthe particles in the selected field of view.

The image is saved in an acceptable file format, such as JPEG, andopened using ImageJ 1.49 v (Image Processing and Analysis in Java)computer software using the “File/Open” menu pointed to the stored filedirectory.

Next, adjust the settings on ImageJ. Open the threshold settings paneland select the following: method (Default), Color (B&W), and Color Space(HSB).

The next step is to tune the white background and black particles tomake sure that the images to be studied are completely filled within theoutline masks. This is done using the brightness sliders in the softwareprogram. Slide the brightness slider so snow appears in the background,as in FIG. 9A. Then, slide the brightness adjustments just until thebackground becomes white again, without any snow, as in FIG. 9B.

The image is ready for measurement processing. Using the “SetMeasurements” menu, assign the measurements t be taken for the image.For this test, “Shape descriptors” must be checked for circularity androundness measurements. Then, use the “Analyze Particles” command fromthe “Analyze” menu to select a size filter, to omit any small particlesto not be included in measurement. This is done by selecting size(pixel{circumflex over ( )}2): 500-Infinity. In the “Analyze Particles”command, also select display results, clear results, summarize, excludeon edges, and include holes. Exclude on edges will not include anythresholded particles on the edge of the image, only those within fullview. Also select Show: “Overlay Outlines” to create new image withanalyzed particles highlighted for easy reference. Now, select “OK” toanalyze the particles. An image summary report and outline overlay ofthe original image will be displayed.

Repeat ten times with each population of particles, changing the fieldof view each time and calculate the mean circularity.

Tables 10-14, below, show the treatments used in Examples 1-4.

TABLE 10 Example 1 Treatments Treatment 1 Treatment 2 Treatment 3Treatment 4 PE Coated 700 g 700 g 700 g 700 g Cellets Eudragit ® 1020.9g 1020.9 g 1084.7 g 1212.0 g FS 30D¹ Eudragit ® 180.6 g 180.6 g 120.8 g0 g L30D-55² Polysorbate 80 3.5 g 3.5 g 3.6 g 3.6 g Triethyl Citrate20.7 g 20.7 g 19.9 g 18.0 g Glycerol 15.0 g 15.0 g 14.9 g 14.4 gMonostearate Purified Water 758.8 g 758.8 g 756.4 g 752.0 g TotalSolution 1999.5 g 1999.5 g 2000.3 g 2000.0 g Grams Sprayed 1028.7 g1732.3 g 1043.7 g 1029.2 g Target Batch 905.6 g 1046.2 g 908.7 g 905.6 gSize Wt % Increase 29.4% 49.5% 29.8% 29.4% Wt % of pH 22.7% 33.1% 23.0%22.7% Sensitive Coating ^(1,2)Available from Evonik Industries(Darmstadt, Germany)

TABLE 11 Examples 2 and 4 Treatments C, A, and D 10 mg IR/3 mg 10 mgIR/5 mg 10 mg IR/5 mg delayed release delayed release delayed release(50% pH coating) (40% pH coating) (50% pH coating) capsules capsulescapsules Treatment C A D % mg % mg % mg Delayed Release ParticlePhenylephrine HCl 2.62 3 4.38 5 4.07 5 Cellets 500 (microcrystalline55.55 63.67 58.23 66.43 54.1 66.43 cellulose core) Kollicoat ® IR(solids) 3.81 4.36 4.1 4.67 3.81 4.67 Talc 1.9 2.18 2.05 2.34 1.9 2.34Eugradit FS30D 31.94 36.6 27.5 31.38 31.94 39.22 PlasACRYL ™ T20 3.193.66 2.75 3.14 3.19 3.92 (Triethyl Citrate) 1.68 1.92 1.44 1.65 1.682.06 (Glycerol monostearate 1.34 1.54 1.15 1.32 1.34 1.65 (Polysorbate80) 0.18 0.2 .15 .18 .18 0.22 Aerosil ® 200 (SiO2) 0.99 1.13 0.99 1.130.99 1.22 Immediate Release Particle Phenylephrine HC1 8.66 10 8.66 108.66 10 Cellets 500 (microcrystalline 81.51 94.17 81.51 94.17 81.5194.17 cellulose core) Kollicoat ® IR (solids) 5.9 6.81 5.9 6.81 5.9 6.81Talc 2.95 3.41 2.95 3.41 2.95 3.41 Aerosil ® 200 (SiO2) 0.99 1.14 0.991.14 0.99 1.14

TABLE 12 Examples 2 and 4 Treatments F, B, and E 10 mg IR/5 mg 10 mgIR/7 mg 10 mg IR/7 mg delayed release delayed release delayed release(60% pH coating) (40% pH coating) (50% pH coating) capsules capsulescapsules Treatment F B E % mg % mg % mg Delayed Release ParticlePhenylephrine HCl 3.8 5 6.01 7 5.58 7 Cellets 500 (microcrystalline50.51 66.43 56.6 65.92 52.58 65.92 cellulose core) Kollicoat ® IR(solids) 3.55 4.67 4.1 4.77 3.81 4.77 Talc 1.78 2.34 2.05 2.39 1.9 2.39Eugradit FS30D 35.79 47.06 27.5 32.03 31.94 40.04 PlasACRYL ™ T20 3.584.71 2.75 3.2 3.19 4 (Triethyl Citrate) 1.88 2.47 1.44 1.68 1.68 2.1(Glycerol monostearate 1.5 1.97 1.15 1.34 1.34 1.68 (Polysorbate 80) 0.20.26 .15 .18 .18 0.22 Aerosil ® 200 (SiO2) 0.99 1.3 0.99 1.15 0.99 1.24Immediate Release Particle Phenylephrine HCl 8.66 10 8.66 10 8.66 10Cellets 500 (microcrystalline 81.51 94.17 81.51 94.17 81.51 94.17cellulose core) Kollicoat ® IR (solids) 5.9 6.81 5.9 6.81 5.9 6.81 Talc2.95 3.41 2.95 3.41 2.95 3.41 Aerosil ® 200 (SiO2) 0.99 1.14 0.99 1.140.99 1.14

TABLE 13 Example 3 Treatments A and B 10 mg IR/10 mg 10 mg IR/15 mgdelayed release delayed release (45% pH Coating) (45% pH Coating)capsules capsules Treatment A B % mg % mg Delayed Release FillPhenylephrine HCl 7.91 10.00 11.11 15.00 Cellets 500 (microcrystalline52.02 65.76 48.82 65.91 cellulose core) Kollicoat IR (solids) 4.20 5.304.20 5.66 Talc 2.10 2.65 2.10 2.83 Eugradit FS30D 29.80 37.67 29.8040.23 PlasACRYL T20 2.98 3.77 2.98 4.02 (Triethyl Citrate) 1.56 1.981.56 2.11 (Glycerol monostearate 1.25 1.58 1.25 1.69 (Polysorbate 80)0.17 0.21 0.17 0.23 Aerosil 200 (SiO2) 0.99 1.25 0.99 1.34 ImmediateRelease Fill Phenylephrine HCl 8.60 10.00 8.60 10.00 Cellets 500(microcrystalline 81.00 94.17 81.00 94.17 cellulose core) Kollicoat IR(solids) 6.27 7.29 6.27 7.29 Talc 3.14 3.65 3.14 3.65 Aerosil 200 (SiO2)0.99 1.15 0.99 1.15

TABLE 14 Example 3 Treatments C and D 10 mg IR / 20mg 15mg IR / 15mgdelayed release delayed release (45% pH Coating) (45% pH Coating)capsules capsules Treatment C D % mg % mg Delayed Release FillPhenylephrine HCl 11.11 20.00 11.11 15.00 Cellets 500 (microcrystalline48.82 87.87 48.82 65.91 cellulose core) Kollicoat IR (solids) 4.20 7.554.20 5.66 Talc 2.10 3.78 2.10 2.83 Eugradit FS30D 29.80 53.64 29.8040.23 PlasACRYL T20 2.98 5.36 2.98 4.02 (Triethyl Citrate) 1.56 2.811.56 2.11 (Glycerol monostearate 1.25 2.25 1.25 1.69 (Polysorbate 80)0.17 0.30 0.17 0.23 Aerosil 200 (SiO2) 0.99 1.78 0.99 1.34 ImmediateRelease Fill Phenylephrine HCl 8.60 10.00 11.83 15.00 Cellets 500(microcrystalline 81.00 94.17 77.77 98.64 cellulose core) Kollicoat IR(solids) 6.27 7.29 6.27 7.95 Talc 3.14 3.65 3.14 3.98 Aerosil 200 (SiO2)0.99 1.15 0.99 1.26

Examples 1-4 were made as follows. First, 7000 grams (g) of Cellets 500(available from Glatt® Air Techniques Inc., Ramsey, N.J.) were spraycoated with an aqueous solution containing 1235.0 g phenylephrinehydrochloride dissolved in 11,115 g of purified water and then dried ina GPCG-5 fluid bed column with 9 inch Wurster Insert (available fromGlatt® Air Techniques, Ramsey, N.J.). The fluid bed column was attachedto a calibrated pump set at a constant rate of 20-60 grams per minute.The Cellets® with the aqueous coating were then dried in the fluid bedcolumn for five minutes at 20 cubic feet per minute (CFM) at atemperature between 35 degrees Celsius (° C.) and 45° C. to form thephenylephrine hydrochloride (PE-HCl) coated Cellets®.

In a separate container, polysorbate 80, triethylcitrate, andglycerolmonostearate were combined in 540 g of purified water. Thepolysorbate 80, triethylcitrate, and glycerolmonostearate mixture washeated by a hot plate between 70° C. and 80° C. and stirred with apropeller mixer. After the ingredients were dissolved, the solution wascooled to room temperature, which was less than 33° C., and purifiedwater was added to produce approximately 2000 g of solution. In Example1, 212 g of purified water was added so the total solution weighed 2000g. Then the Eudragit® FS-30D was added to the solution (available fromEvonik Industries, Darmstadt, Germany) and was stirred with a propellermixer for 60 min to form Dispersion 1.

In Example 1, Dispersion 1 was sprayed onto 700 g of the PE-HCl coatedCellets® using a calibrated pump sprayer attached to a fluid bed columnset to a rate between 20-60 grams per min. The spray coating wasperformed within the GPCG-5 fluid bed column with a 6″ Wurster insert at45±10° C. 905.6 g of coated particles were obtained after drying for 5min in the same fluid bed column with an air inlet temperature of 45±10°C.

For Examples 2, 3, and 4 the process of dissolving the polysorbate 80,triethylcitrate, and glycerolmonosterate from above was repeated andthen the Eudragit® L30D-55 was added as described above to formDispersion 2.

In Examples 2, 3, and 4, Dispersion 1 and 2 were combined into a singlecontainer and stirred at room temperature for 45 minutes using apropeller mixer. The final volume was adjusted with purified water toproduce approximately 2000 g of the combined total solution. Thecombined total solution was then screened through a US 60 mesh screeninto a clean container and stored at room temperature and was stirredcontinuously until use. The combined total solution was used within 48hours after it was screened.

Next, the combined total solution was sprayed onto 700 g of the PE-HClcoated Cellets® and dried for five minutes as described above. 900-1050grams, depending on the weight percent of the coating, of coatedparticles were obtained after drying for five minutes as describedabove.

Examples 5-15 include both immediate release and delayed releaseparticles. As a first step, drug layered particles were produced using abatch size of 7000 g of Cellets® 500. PE-HCl spray solutions wereprepared in an appropriately sized vessel with mixing element viadissolving PE-HCl in water to produce a 22.5% concentrated solution.Depending on the example, particles were drug layered in a GPCG-5 fluidbed with 9″ Wurster insert to yield particles having a final PE-HClconcentration of 4.5%, 7.0%, 9.6%, 13.2%, and 18.54%. The processconditions for drug layering included a 55° C. inlet air temperature,40° C. product temperature, 150 CFM air flow rate, and ramping to a 26g/min spray rate.

After a one minute drying step, the drug layered particles from examples5-11 are then seal coated with a coating spray of 15% Kollicoat® IR and7.5% talc to a weight gain of 7% based on the Kollicoat® IR polymer. Thespray composition is prepared as follows: 59% of the total water wasadded to an appropriate sized vessel with a propeller mixer. Kollicoat®IR was added while mixing for a minimum of 15 minutes. In a separatecontainer, the remaining water is added and set-up with a high shearmixer. The talc was added and mixed to form a dispersion for a minimumof 5 minutes. The talc dispersion was then added to the Kollicoat®mixture and mixed for at least 10 minutes with the propeller mixer. TheWurster process conditions in the same equipment included a 52° C. inletair temperature, 42° C. product temperature, 180 CFM air flow rate, andramping to a 17 g/min spray rate. The seal coated particles were thendried for 5 minutes before discharging or further processing.

Some of the 9.6% PE seal coated particles were topcoated with a 5%Aerosil® 200 suspension to a 1% wt. gain using process conditions in thesame equipment having a 53° C. inlet air temperature, 40° C. producttemperature, 170 CFM air flow rate, and ramping to a 20 g/min sprayrate. The top coated particles were dried for 5 minutes. The 5% Aerosil®200 suspension was prepared by adding water to an appropriate sizedcontainer that includes a propeller mixer. This version is for theimmediate release particle.

The other lots were enteric coated to specified wt. gain of entericpolymer using the GPCG-5 fluid bed with 7″ wurster at a batch size of 2kg of the seal coated particles (vide supra). The enteric coateddispersion is made as follows: Water was added to PlasACRYL™ T200 andmixed for 10 minutes minimum in an appropriate sized mixing vessel withtri-blade mixer. While mixing, the Eudragit® FS30D polymer was added andmixed for 5 minutes minimum to make a uniform dispersion. The mixturewas passed through a #60 US standard sieve to remove any clumps present.The process conditions used include a 39° C. inlet air temperature, 30°C. product temperature, 160 CFM air flow rate, and ramping to a 22 g/minspray rate. The enteric coated particles were dried for one minute.

The enteric coated particles were then top coated with a 5% Aerosil® 200suspension (made as above) to a 1% wt. gain using process conditions inthe same equipment having a 39° C. inlet air temperature, 30° C. producttemperature, 160 CFM air flow rate, and ramping to a 18 g/min sprayrate. The top coated particles were then dried for 5 minutes. Thisversion is for the delayed release particle.

The dimensions and values disclosed herein are not to be understood asbeing strictly limited to the exact numerical values recited. Instead,unless otherwise specified, each such dimension is intended to mean boththe recited value and a functionally equivalent range surrounding thatvalue. For example, a dimension disclosed as “40 mm” is intended to mean“about 40 mm.”

Every document cited herein, including any cross referenced or relatedpatent or application is hereby incorporated herein by reference in itsentirety unless expressly excluded or otherwise limited. The citation ofany document is not an admission that it is prior art with respect toany invention disclosed or claimed herein or that it alone, or in anycombination with any other reference or references, teaches, suggests ordiscloses any such invention. Accordingly, all numerical values areunderstood to be modified by the term “about.” Further, to the extentthat any meaning or definition of a term in this document conflicts withany meaning or definition of the same term in a document incorporated byreference, the meaning or definition assigned to that term in thisdocument shall govern.

While particular embodiments of the present invention have beenillustrated and described, it would be obvious to those skilled in theart that various other changes and modifications can be made withoutdeparting from the spirit and scope of the invention. It is thereforeintended to cover in the appended claims all such changes andmodifications that are within the scope of this invention.

What is claimed is:
 1. A method for temporarily relieving sinuscongestion and pressure comprising administering to a human a dose of amulti-particle pulsatile oral dosage form comprising: a. an immediaterelease form comprising from about 10 mg to about 20 mg phenylephrine ora pharmaceutically acceptable salt thereof; and b. a plurality ofdelayed release particles; wherein each delayed release particlecomprises: i. a core wherein at least about 85% of the cores comprise adiameter from about 500 μm to about 710 μm; ii. a phenylephrine coatingcomprising phenylephrine hydrochloride; iii. a pH sensitive coatingcomprising an acrylate copolymer selected from the group consisting ofmethyl-methacrylate esters copolymerized with methacrylic acid, acrylicacid and esters copolymerized with methacrylic acid and esters,ammonio-containing acrylate copolymers, and combinations thereof;wherein the pH sensitive coating is from 10 μm to about 80 μm thick;wherein the plurality of delayed release particles comprise from about 7mg to about 15 mg phenylephrine or a pharmaceutically acceptable saltthereof.
 2. The method of claim 1 wherein the pH sensitive coatingcomprises poly(methyl acrylate-co-methyl methacrylate-co-methacrylicacid) 7:3:1 polymer.
 3. The method of claim 2 wherein the pH sensitivecoating is from about 25 μm to about 55 μm thick.
 4. The method of claim2 wherein the pH sensitive coating is from about 30 μm to about 45 μmthick.
 5. The method of claim 1 wherein each delayed release particlefurther comprises a separation coating between the phenylephrine coatingand the pH sensitive coating.
 6. The method of claim 5 wherein theseparation coating is selected from the group consisting of talc,polyvinyl alcohol-polyethylene glycol graft co-polymer, hydroxypropylymethylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidine, andcombinations thereof.
 7. The method of claim 1 wherein the plurality ofdelayed release particles comprise about 10 mg phenylephrinehydrochloride.
 8. The method of claim 1 wherein the core is selectedfrom the group consisting of microcrystalline cellulose, sugars,starches, polymers, and combinations thereof.
 9. The dose according toclaim 8 wherein the core comprises microcrystalline cellulose.
 10. Themethod of claim 1 wherein the pulsatile dosage form comprises a Cmax2,an AUC₀₋₄ and an AUC₄₋₈, wherein the Cmax2, the AUC₀₋₄ and the AUC₄₋₈for the pulsatile dosage form meets or exceeds systemic exposuresrelative to two sequential doses of an immediate release phenylephrinetaken four hours apart.
 11. The method of claim 1 wherein the dose canbe readministered every eight hours, up to three times per day, ifsymptoms persist.
 12. A method for temporarily relieving sinuscongestion and pressure comprising administering to a human a dose of amulti-particle pulsatile oral dosage form comprising: a. an immediaterelease form comprising from about 10 mg to about 20 mg phenylephrine ora pharmaceutically acceptable salt thereof; and b. a plurality ofdelayed release particles; wherein each delayed release particlecomprises: i. a core; ii. a phenylephrine coating comprisingphenylephrine hydrochloride; iii. a pH sensitive coating wherein the pHsensitive coating comprises an enteric coating; wherein the pH sensitivecoating is from 10 μm to about 80 μm thick; wherein the plurality ofdelayed release particles comprise from about 7 mg to about 15 mgphenylephrine hydrochloride; wherein the pulsatile dosage form comprisesa C_(max2) and an AUC₄₋₈ wherein an upper bound of a 90% confidenceinterval for a ratio of means for the C_(max2) and the AUC₄₋₈ of thepulsatile dosage form relative to two sequential doses of an immediaterelease phenylephrine taken four hours apart is at least 85%.
 13. Themethod of claim 12 wherein the pH sensitive coating comprises one ormore polymers with a weight average molecular weight from about 225,000g/mol to about 350,000 g/mol.
 14. The method of claim 12 wherein thecore is substantially free of phenylephrine.
 15. The method of claim 12wherein the pH sensitive coating is from about 25 μm to about 55 μmthick.
 16. The method of claim 12 wherein the pH sensitive coating isfrom about 30 μm to about 45 μm thick.
 17. The method of claim 12wherein at least one delayed release particle comprises a meancircularity from about 0.7 to about 1 as determined by the SmoothnessTest Method.
 18. The method of claim 12 wherein the pulsatile dosageform further comprises a C_(max1) and wherein a ratio of a mean C_(max2)to a mean C_(max1) is from about 125% to about 225%.
 19. The method ofclaim 12 wherein the pulsatile dosage form further comprises a C_(8 hr)wherein a mean C_(8 hr) is from about 120% to about 175% of a meanC_(8 hr) of two sequential doses of an immediate release phenylephrinetaken four hours apart.